Shared pan-cancer antigens

Abstract

The present invention relates to tumor antigens encoded by dark genome elements as nucleic acid encoding thereof, composition comprising thereof including vaccine composition, and antigen binding molecules targeting thereof. The present invention also encompasses well as the use of the nucleic acid encoding thereof, composition comprising thereof including vaccine composition, and antigen binding molecules targeting thereof as immunotherapeutic agent for the treatment and / or the prevention of cancer.

Description

SHARED PAN-CANCER ANTIGENSTECHNICAL FIELDThe present disclosure generally relates to cancer, and more specifically to shared tumor specific antigens useful for immunotherapy.BACKGROUND ARTIdentifying and harnessing cancer antigens that drive effective immune system activation is thus critical for the success of immunotherapy. Targeting of MHC associated peptides presented at the surface of tumor cells have broadly extended the reservoir of targetable antigens. However, broad patient coverage remains a paramount towards development of standardized and accessible therapeutic strategies that have the ability to be effective in a large percentage of patients.A pressing need thus remains to identify shared tumor specific antigens that can elicit therapeutic immune responses with a large therapeutic scale. Such tumor antigens could be used as vaccines (± immune checkpoint inhibitors) or as targets for T-cell receptor-based approaches (e.g., including cell therapy, and multispecific biologicals such as T cell engagers).Furthermore, identification of tools usable in methods for diagnosis, prognosis or personalized cancer treatment of patients remains a pressing need.SUMMARY OF THE DISCLOSUREThe inventors now provide a technical solution to the previously raised problem and disclose herein target polypeptides derived from a dark genome region (i.e. typically annotated as an “untranslated region” in Ensembl or in the Human Genome Browser (hgl9 or hg38 assembly) that are expressed at low or undetectable levels in healthy tissues while being overexpressed in multiple tumor tissues. These transcripts are not only recurrently expressed in cancer tissues but are also shared among a large proportion of cancer patients.The inventors have further shown that polypeptide sequences derived from these transcripts can be translated, processed by components of the antigen-processing apparatus, and presented on the surface of cancer cells in association with the class I major histocompatibility complex (MHC Class I) molecules. These MHC-associated peptides (MAPs) and polypeptides comprising thereof are therefore of high interest for the development of immunotherapies (including vaccine and binderbased therapies).The inventors have further developed molecular tools and methods for the detection of these newly identified tumor specific targets, both at the transcriptomic and peptidomic levels. These tools andmethods are usable in diagnosis and prognosis methods, as well as companion assays of cancer therapies (in particular for the treatment of cancers, positive for one or more of the target polypeptides or MAPs of the present disclosure).Lastly the inventors have for the first time developed scFv-based binders and binders constructs (including CAR and TCEs) that specifically target this peptide and provided strong evidence that this TE-derived peptide can be targeted to kill tumor cell expressing thereof and achieve tumor regression and / or control.The present disclosure therefore encompasses an isolated polypeptide comprising a target amino acid sequence having at least 8 amino acid residues and which is characterized as follow:the target amino acid sequence is encoded by a nucleic acid molecule derived from the gene NIHCOLE as referenced in table 1 ;the target amino acid sequence is encoded by a nucleic acid comprising a sequence of any one of SEQ ID NO: 1-55, a fragment or a variant thereof;the target amino acid sequence is of any one of SEQ ID NO:56-1032, a fragment or a variant thereof; orthe target amino acid sequence is of any one of SEQ ID NO: 1033-1140, or a variant thereof. In some embodiments, the polypeptide can be a recombinant or synthetic polypeptide.In some embodiments, the polypeptide comprises a target amino acid sequence that does not comprise, or that does not consist in, a sequence that derives from the gene NIHCOLE and that is also annotated as a LINE transposable element. In some embodiments, the target amino acid sequence does not comprise, or does not consist in, a sequence from the LINE repeat element L1PA2 located at chr5: 103,410,064-103,416,082 (GRCh37).In some embodiments, the polypeptide comprises a target sequence that is encoded by a splice variant transcript of the NIHCOLE gene, or a fragment thereof which comprises the junction of coordinates chr5: 103,416,742-103,417,581 forward strand (GRCh37).In some embodiments, the polypeptide comprises a sequence selected from any one of:SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO: SEQ ID NO:1033 1079 1094 1106 11211034 1081 1095 1107 11221038 1082 1096 1108 11231039 1083 1098 1109 11271047 1084 1099 1110 11281062 1086 1101 1111 11291064 1088 1102 1112 11311073 1089 1103 11161077 1090 1104 11171078 1092 1105 1120variant sequences and fragments thereof, notably selected from any one of SEQ ID NO: SEQ ID NOs:1034, 1064, 1089, 1101 and 1131, fragments and variants thereof; optionally wherein the polypeptide comprises or consists of the sequence SEQ ID NOs:1034, 1064, 1089, 1101 and 1131.The present disclosure further encompasses a polynucleotide encoding the above defined polypeptide as well as a vector comprising thereof.The present disclosure also provides a molecular complex comprising an MHC associated peptide (MAP) having a sequence of 8 to 15 amino acid residues from a polypeptide as defined previously and an MHC type I molecule, wherein the polypeptide binds to the said MHC molecule with a KD binding affinity of 10'6M or less or an IC50 of less than 500 nM.In some embodiments, the molecular complex comprises an HLA-A*03 or an HLA-A* 11 molecule and a MAP of 8 to 15 amino acids residues (i) comprising or consisting in the amino acid sequence of SEQ ID NO: 1034 (MUH peptide) or a variant thereof, and (ii) binding to the said HLA-A*03 and / or an HLA-A*011 molecule with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM.In some embodiments, the molecular complex comprises an HLA-A*03 or an HLA-A* 11 molecule and a MAP of 8 to 15 amino acids residues (i) comprising or consisting in the amino acid sequence of SEQ ID NO: 1064 (MUH peptide) or a variant thereof, and (ii) binding to the said HLA-A*03 and / or an HLA-A*011 molecule with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM, optionally wherein the MAP consists in SEQ ID NO: 1089.In some embodiments, the molecular complex comprises an HLA-A* 02 molecule, and a MAP of 8 to 15 amino acids residues (i) comprising or consisting in the amino acid sequence of SEQ ID NO: 1089 or a variant thereof, and (ii) binding to the said HLA-A*02 with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM; optionally wherein the MAP consists in SEQ ID NO: 1089.In some embodiments, the molecular complex comprises an HLA-A*02 molecule, and a MAP of 8 to 15 amino acids residues (i) comprising or consisting in the amino acid sequence of SEQ ID NO: 1101 or a variant thereof, and (ii) binding to the said HLA-A*02 with a KD binding affinity of10'6M or less or with an IC50 of less than 500 nM; optionally wherein the MAP consists in SEQ ID NO:1101.In some embodiments, the molecular complex comprises an HLA-A*02 molecule, and a MAP of 8 to 15 amino acids residues (i) comprising or consisting in the amino acid sequence of SEQ ID NO: 1131 or a variant thereof, and (ii) binding to the said HLA-A*02 with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM; optionally wherein the MAP consists in SEQ ID NO:1131.In some embodiments, the HLA molecule and the peptide are operatively linked through a peptide bond, or through van der Waals forces.In some embodiments, the HLA molecule and / or the peptide are conjugated to a detection tag. In some embodiments, at least two peptide-MHC complexes are operatively linked to each other. The present disclosure also relates to a composition, notably a pharmaceutical composition comprising the molecular complex as herein defined.The present disclosure further provides a cell expressing a polynucleotide as herein defined, and / or expressing at his cell surface a polypeptide and / or a molecular complex as previously defined; optionally wherein the cell is a cell line, notably a cancer cell line; optionally wherein the cell is an antigen presentation cell (APC), notably a dendritic cell, optionally wherein the APC is in vitro isolated; optionally wherein the peptide and / or the HLA molecule of the HLA complex is recombinantly expressed.In some embodiments, the cell as previously mentioned is an antigen presenting cell (APC) expressing at its cell surface one or more MAP(s) having a sequence of 8 to 15 amino acid residues from a polypeptide as previously, optionally wherein the APC has been pulsed with the said one or more MAP or wherein the APC has been transfected with the said or more MAP(s), optionally wherein the APC is expressing one or more MHC molecule that bind with the said one or more MAP with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM; optionally wherein the APC is a dendritic cell.The present disclosure also provides a composition comprising a polypeptide according to the present disclosure, a polynucleotide, a vector, a molecular complex; and / or a cell as above defined; optionally wherein the composition is a pharmaceutical composition; optionally wherein when the composition comprises a molecular complex as above defined, the HLA molecule and / or thepeptide is conjugated to a detection tag; optionally wherein when the composition comprises a molecular complex as previously defined, .In some embodiments, at least two peptide-MHC complexes are operatively linked to each other. The present disclosure also relates to a composition, notably a pharmaceutical composition comprising the molecular complex as herein defined.The present disclosure further encompasses a cell expressing at his cell surface the molecular complex as herein described. Typically, the cell is a cell line, notably a cancer cell line or an antigen presentation cell (APC), notably a dendritic cell. The antigen presenting cell can be in vitro isolated and / or engineered. In some embodiments, the peptide and / or the HLA molecule of the HLA complex are recombinantly expressed.The present disclosure further provides an antigen binding protein (ABP) that specifically binds a polypeptide or MAP as previously defined (optionally in association with an MHC molecule with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM), and / or with the molecular complex as previously defined. In some embodiments, the ABP essentially consists in an antibody, a TCR or a variant thereof and the said ABP binds the said polypeptide or molecular complex with a KD binding affinity of 10'6M or less (preferably comprised between 0.1 to 100 10"9M). In some embodiments, the ABP is a multispecific antibody, a CAR or an antibody drug conjugate (ADC); in particular the multispecific antibody is a T cell engager (TCE) or an NK cell engager (NKCE). In specific embodiments, the ABP is a chimeric TCR.In some embodiments the ABP comprises a VH and a VL as defined in Table 3, notably: (i) a VL of SEQ ID NO: 1177 and a VH of SEQ ID NO: 1170; (n) a VL of SEQ ID NO: 1193 and a VH of SEQ ID NO: 1186; (m) a VL of SEQ ID NO: 1209 and a VH of SEQ ID NO: 1202; (iv) a VL of SEQ ID NO: 1150 and a VH of SEQ ID NO: 1143; (v) a VL of SEQ ID NO: 1225 and a VH of SEQ ID NO:1218.In some embodiments the ABP comprises light chain CDRs (LCDR1-3) and heavy chain CDRs (HCDR 1-3) as defined in Table 4.In some embodiments, the ABP comprises an scFv of any one of SEQ ID NO: 1169, 1185, 1201 or 1217.The present disclosure further encompasses one or more nucleic acids or a vector comprising thereof encoding the peptide or an ABP as herein disclosed. For example, where the ABP is a multisubunit ABP, the ABP may be encoded by multiple nucleic acids, each encoding a subunit. Inpreferred embodiments, the ABP comprises 2, or 4 chains and is therefore encoded by 2 or 4 nucleic acid sequences. The one or more nucleic acid sequences may be on the same or different vectors.The present disclosure also encompasses one or more nucleic acid probes that specifically bind to the nucleic acid encoding a polypeptide (e.g. as defined in Table 8 herein notably a polypeptide of any one of SEQ ID NO: 72332, 405, 555, or 948) notably a MAP as herein defined (e.g as defined in Table 9, e.g. a MAP of any one of SEQ ID NOs: 1034, 1064, 1089, 1101 and 1131).The present disclosure also encompasses one or more nucleic acid primer that specifically amplify the nucleic acid encoding a polypeptide (e.g. as defined in Table 8 herein notably a polypeptide of any one of SEQ ID NO: 72332, 405, 555, or 948) notably a MAP as herein defined (e.g as defined in Table 9, e.g. a MAP of any one of SEQ ID NOs: 1034, 1064, 1089, 1101 and 1131).In some embodiments, the one or more probe(s) and / or primer comprise or consists in a sequence of Tables 11 and 15 and or target or specifically hybridize with a sequence of Table 12.The present disclosure also encompasses one or more probe(s) and / or primer(s) specifically hybridizing with nucleic acid encoding a polypeptide (e.g. as defined in Table 8 herein notably a polypeptide of any one of SEQ ID NO: 72332, 405, 555, or 948) notably a MAP as herein defined (e.g as defined in Table 9, e.g. a MAP of any one of SEQ ID NOs: 1034, 1064, 1089, 1101 and 1131). In preferred embodiments, the one or more probes comprise a sequence that specifically hybridizes with a sequence of Table 12.The present disclosure also encompasses oligonucleotide therapeutic agents, e.g. RNA interfering agents or guide RNA (gRNA typically from CRISPR systems), that bind to DNA or RNA poly nucleotide sequences encoding the peptide. In some embodiments, the present disclosure encompasses targeting the sequences as defined in Table 14. gRNAs targeting these sequences can be used for specific knock-out NIHCOLE exon 3, or NIHCOLE exon 2 and exon3 (using a combination of gRNAs targeting AA and AC sequences). gRNA can be used as cRNA in a crRNA:tracrRNA duplex format or as a single molecule made of the fusion of the crRNA and the tracRNA.The present disclosure also encompasses, a cell, notably an immune cell, comprising said nucleic acid or vector. In some embodiments, the cell is an immune cell; optionally wherein the immune cell is selected from NK cells, B cells, antigen presenting cells (APCs), such as monocytes, macrophages, or dendritic cells, sub-types and subpopulations of T cells (including alpha / beta T cells and gamma / delta T cells) and progenitors thereof. T cell subtypes typically include CD4+ T cells, CD8+ T cells, CD4+ and CD8+ T cells, T regulatory cells (Treg), Naive T cells (TN cells),effector T cells, memory stem T cells (TSCMs), memory T cells (TCMs), effector memory T cells (TEM cells), resident memory T cells (TCRMs), mucosa-associated invariant T (MATT), and NK T cells (NKT cells). Progenitors, notably T cell progenitors, include lymphoid progenitors, myeloid progenitors, pluripotent stem cells, and induced pluripotent stem cells (iPSCs) as well as hematopoietic stem cells (HSCs), adipose derived stem cells (ADSCs), or pluripotent stem cells of myeloid or lymphoid lineage.Also included herein is a composition comprising an ABP, a nucleic acid, a vector or a cell. In some embodiments, the composition is a pharmaceutical composition, notably an immunogenic or vaccine composition, notably a composition comprising at least one pharmaceutical adjuvant and / or a carrier.Also included herein is a therapeutic agent consisting in a polypeptide, a polynucleotide (nucleic acid), a vector comprising thereof, a molecular complex, a cell, an ABP, a composition comprising thereof, or a combination thereof, for use as a medicine; notably for use as a medicine in the treatment of a patient suffering from a cancer or a tumor. The cancer or the tumor is notably a solid cancer or tumor, notably selected from a lung tumor or cancer, a cancer or tumor from the digestive system (notably a gastro-intestinal cancer as herein defined), an ovarian or an endometrial cancer or tumor, a liver cancer or tumor, or a pancreatic cancer or tumor.In some embodiments, cancer (or tumor) is positive for the expression a polypeptide and / or for a polynucleotide encoding thereof as herein defined. In some embodiments, the subject has been determined to have a cancer that is positive for the expression of the said polypeptide and / or polynucleotide encoding thereof. In some specific embodiments, the polypeptide or fragment thereof comprises an amino acid sequence that binds an HLA A*02, A*03, and / or A*11 molecule and the patient is selected or known to express one or more of the said HLA molecules. In some specific embodiments, the polynucleotide or fragment thereof code for a MAP that binds an HLA A*02, A*03, and / or A*11 molecule and the patient is selected or known to express one or more of the said HLA molecules.A polypeptide according to the present disclosure can be used, optionnally in association with an MHC molecule, with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM, for the screening of a binding protein or for assessing the specificity of a binding protein targeting thereof. In some embodiments, the binding protein is selected or considered as specific for the said target polypeptide and / or molecular complex when it binds to the said target polypeptide and / or molecular complex with a KD binding affinity of 10'6M or less, preferably comprised between 0.1 to 100 10'9M.In some embodiments, the screening comprises the steps of (i) contacting the antigen-binding protein with the said target polypeptide (or MAP) and / or target molecular complex, optionally wherein the said target polypeptide and / or complex is linked to a solid support or presented at a cell surface, and (ii) recovering the antigen-binding protein which is bound to the said target polypeptide and / or complex; optionally wherein steps a) and b) are repeated one or more times.In some embodiments, the screening can comprise one or more steps for assessing cross-reactivity against one or more counter-selection peptides chosen among peptides of 8 to 12, notably 9 to 12 or 10 to 12 amino acid residues. Preferably, the counter selection peptide and / or a transcript encoding thereof (also named cross-reactive peptide) are known to be expressed healthy tissues. Preferably also, the counter selection peptide binds the HLA molecule of the target molecular complex with an IC50 of 500 nM, or less notably of 50 10'9M or less. Preferably, the counter selection peptide exhibits at least 50 % similarity with the target MAP sequence.In some embodiments, the ABPs does not cross react or reacts less than 20 %, notably less than 15%, less than 10%, or less than 5 % of the levels of the target peptide MHC molecular complex with a molecular complex comprising a counter peptide (also named similar peptide) from a protein or a peptide that is expressed in healthy tissues, optionally wherein any cytotoxic response to said molecular complex comprising a similar peptides from a protein or a peptide that is expressed in healthy tissues is less than 30%, notably less than 20 %, notably less than 10 %, notably less than 5 % of the cytotoxic response obtained with the target molecular complex.Optionally the MAP binds an HLA A*03:01 molecule with an IC50 of 500 nM, or less notably of 50 10'9M or less and have at least 50 % similarity with the sequence MIHI peptide, In some embodiments, counter-selection peptides for the MIHI-HLA A3:01 target molecular complex can be selected from the peptides of Table 13.In some embodiments, the one or more counter-selection peptides are chosen among peptides of 8 to 15 amino acid residues, (i) that bind an MHC that is identical to the MHC molecule of the target molecular complex (i.e. comprising the said target polypeptide), with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM and (ii) that have at least 50 % similarity with the target polypeptide or MAP of the molecular complex. In more specific embodiments, the said counter selection peptide is further known to be presented at the surface of one or more healthy human cell(s) in association with the said MHC molecule.The present disclosure also encompasses methods of using a target peptide or target molecular complex of the present disclosure for identifying or purifying an antigen-binding protein specifically binding it, the method comprising the step of(a) immunizing an animal with the said target molecular complex, or (b) contacting a library of different antigen-binding domains or cells displaying different antigen-binding domains with the said target molecular complex, or (c) contacting cell medium or cell extracts with the said target molecular complex;followed by a step of detecting or isolating one or more antigen binding proteins that bind to the said target molecular complex, wherein the ABP preferentially binds the target molecular complex with a KDof 10'6, notably 10'7M or less.The present disclosure further encompasses methods of using the peptide or the complex of the present disclosure in quality control during manufacture of an antigen-binding protein, comprising the step of contacting a batch of ABPs with a target molecular complex, optionally displayed on a cell, and detecting binding, optionally with a KDof 10'6, notably of 10'7M or less. For example, the target peptide, optionally bound to an HLA molecule can be immobilized on a solid surface and binding of the antigen binding protein can be detected using colorimetric or fluorescent signal.The present disclosure also encompasses an in vitro or an ex vivo method of determining whether a subject has cancer or is at risk of a cancer, the method comprising detecting the presence and / or amount of a peptide as defined in prior claim and / or a nucleic acid encoding thereof, in a biological sample harvested from the subject thereby to determine whether the subject has cancer. In more particular embodiments, the detection of the said polypeptide and / or polynucleotide in the said sample harvested from the patient means that the patient has cancer. In some embodiments, the method further comprises the determination of the amount of the said polypeptide and / or polynucleotide in the said sample and its comparison to a reference value, wherein the subject is determined to have a cancer if the determined amount of polypeptide and / or polynucleotide is equal or superior to the reference value.The method can also comprise a step of selecting a treatment regimen based upon the detected presence or amount of polypeptide and / or polynucleotide encoding thereof in the said biological sample from the patient. The treatment can comprise an anti-cancer agent, notably a therapeutic agent previously defined.The present disclosure also encompasses an in vitro or an ex vivo method for identifying a patient, notably an HLA A*02, HLA A*03 and / or HLA-A* 11 -positive cancer patient as likely to benefitfrom a treatment with a therapeutic agent as previously defined and comprising a peptide, a composition, a cell, a nucleic acid and / or an antigen binding protein as herein defined, said method can comprise a step of detecting the expression of a polypeptide or peptide as previously defined and / or nucleic acid encoding thereof in a tumor biological sample from the subject, wherein the patient is likely to benefit from the treatment with the polypeptide or peptide, nucleic acid, vector and / or antigen-binding protein if the polypeptide or peptide and / or nucleic acid encoding thereof is detected in the said tumor sample; optionally, wherein the polypeptide or a fragment thereof comprises a amino acid sequence that binds an HLA A*02, A*03, and / or A* 11 molecule and wherein the patient is selected or known to express one or more of the said HLA molecules .The present disclosure also encompasses an in vitro or an ex vivo method for prognosing a patient or for detecting T cell responses in a patient expressing HLA A*02, A*03, and / or A*11 molecule, wherein the method comprises: contacting a biological sample from the patient with a target polypeptide optionally in association with an MHC molecule as previously defined. In some embodiments, the detection of T cell responses comprises detecting the binding of the peptide or molecular complex to the T cell or TCR, notably wherein the polypeptide or a fragment thereof comprises a amino acid sequence that binds an HLA A*02, A*03, and / or A* 11 molecule and wherein the patient is selected or known to express one or more of the said HLA molecules .In various embodiments of the methods and uses of the present disclosure, the presence or amount of the target polypeptide or peptide, or nucleic acid encoding thereof is determined using an NGS-based assay, a nucleic acid amplification assay, and hybridization assay, such as RNA fish assay, an immuno-assay, a mass spectrometry-based assay, or a combination thereof. Optionally, the cancer or tumor is a solid tumor, notably a gastro-intestinal cancer or tumor, a lung cancer or tumor or an ovarian cancer or tumor.In some embodiments of the methods of the present disclosure, the subject expresses an HLA- A* 02, HLA-A*03 and / or an HLA-A*011 molecule.In various embodiments of the present disclosure, the biological sample is a tissue, a blood sample, a cell line, an organoid, saliva, cerebrospinal fluid, or other bodily fluids harvested from the subject. In some embodiments, the sample is a tumor or cancer sample.The present disclosure further encompasses a kit for detecting the presence of a polypeptide or peptide as herein defined or a polynucleotide encoding thereof as defined herein in a biological sample, or for use in a method of the disclosure. Such a kit typically comprises:- one or more labeled compound(s) or agent(s) capable of detecting the polypeptide or polynucleotide in the biological sample;optionally, means for determining the amount of the polypeptide or polynucleotide encoding thereof in the biological sample; andoptionally, means for comparing the amount of the polypeptide or polynucleotide encoding thereof in the biological sample with a standard (or reference);The compound or agent can be packaged in a suitable container. The kit can also comprise instructions for using the kit to detect the polypeptide of transcript encoding thereof.In some embodiments, the one or more label compounds comprises one or more target polynucleotide sequence(s) comprising a nucleotide sequence of any one of SEQ ID NO: 1249-1255 and / or one or more polynucleotide sequence(s) comprising a nucleotide sequence that specifically hybridize with any one of SEQ ID NO: 1256-1263.The present disclosure further encompasses a target polypeptide or peptide, a molecular complex, an antigen binding protein, a nucleic acid encoding the said, a cell expressing the said, as defined herein, for use in the treatment of cancer, notably wherein the patient is selected to express an HLA A*02, A*03, and / or A*11 molecule, optionally wherein the cancer is a cancer that is positive for the expression of the peptide or a nucleic acid encoding thereof. In some embodiments, the subject has been determined to have cancer that is positive for expression of the polypeptide (or peptide) or a nucleic acid encoding thereof.The present disclosure notably encompasses a pharmaceutical composition for use in the treatment of a patient, notably a patient suffering from a cancer, optionally wherein the treatment comprises steps of determining whether the peptide or a nucleic acid encoding thereof is expressed by tumor cells of the patient and optionally wherein the patient is expressing an HLA A*02, A*03, and / or A* 11 molecule. Such methods may comprise the step of contacting nucleic acids in a biological sample from the patient with a reagent, e.g. suitable probe(s) or primers, which detects the presence or relative quantity of nucleic acid encoding the peptide, optionally including the step of extracting nucleic acids from the sample, and optionally amplifying nucleic acid encoding the peptide. Such methods may also include contacting a biological sample from the patient with an antibody that specifically binds to the peptide.The present disclosure also encompasses a pharmaceutical composition for use according to the present disclosure wherein, the composition is a vaccine composition comprising a peptide, anucleic acid, a molecular complex or an antigen presenting cell exposing it at its cell surface or the present disclosure, or the composition comprises an antigen binding protein, a nucleic acid or an immune cell expressing thereof as defined herein. . In some embodiments, the peptide or the nucleic acid encoding thereof further comprises non-native amino acids or nucleotide sequence flanking its core sequence as defined notably in Tables 8 and 9 (e.g.: SEQ ID NOs:1034, 1064, 1089, 1101 and ORFs comprising thereof of any one of SEQ ID NOs: 1034, 1064, 1089, 1101 and 1131).The present disclosure notably encompasses a pharmaceutical composition comprising:(i) an immunogenic or vaccine composition as herein disclosed;(ii) an antigen binding protein as herein disclosed;(iii) an isolated or recombinant nucleic acid or vector comprising thereof as herein disclosed; (iv) an antigen presenting cells (APCs) as herein disclosed;(v) an activated T cell as herein disclosed; or(vi) an engineered immune cell as herein disclosed; anda pharmaceutically acceptable excipient.BRIEF DESCRIPTION OF THE DRAWINGFigure 1. Figure la shows a schematic of the NIHCOLE gene region with its 12 annotated transcripts from Ensembl hg38. The splicing P12 junction giving rise to the P12 peptide (or MIHI peptide) is annotated as being part of 7 different transcripts of the gene NIHCOLE (isoforms highlighted in bold). The inventors are defining exon 1 as the first exon shared by all transcripts comprising the P12 junction. Figure lb shows a schematic of the cDNA from the P12 junction with the donor (D) and acceptor (A) parts giving rise to P12 peptide (‘or MIHI peptide). Genomic location is from hg!9 assembly.Figure 2. Figure 2a shows the expression of P12 junction in all tumor RNAseq datasets analyzed. Expression is plotted in count per ten million (CPTM = number of splicing reads / total number of unique mapped reads * 10000000) and linear scale. Figure 2b shows the expression of Pl 2 junction in all healthy and juxta tumors RNAseq datasets analyzed. Expression is plotted in CPTM and linear scale. Figure 2c shows the expression of NIHCOLE in all datasets related to gastro-intestinal cancers including, tumors patient samples, tumor cell lines, juxta tumors and healthy samples. Expression is plotted in TPM and linear scale.Figure 3. Figure 3 a shows a schematic of the monomer folding assay. Figure 3b shows the binding of P12 to HLA-A*03.01 and HLA-A*11 measured as percentage of peptide-MHC-I complex formation relative to the respective positive control peptide.Figure 4. Figure 4a shows the targeted mass spectrometry validation of MN0-P12 in LNT229 cell line. Co-elution of both synthetic and endogenous peptides at apex 36.96 min combined with high MS2 coverage of b and y ions (left pattern refers to endogenous peptide while right pattern refers to synthetic spiked peptide) confirms expression of endogenous MN0-P12 in the LNT229 cells. Figure 4b shows the targeted mass spectrometry validation of MN0-P12 in A172 cell line. Coelution of both synthetic and endogenous peptides at apex 35.11 min combined with high MS2 coverage of b and y ions (left pattern refers to endogenous peptide while right pattern refers to synthetic spiked peptide) confirm expression of endogenous MN0-P12 in the A 172 cells.Figure 5. Figure 5a shows the design of the primers and probes to detect NIHCOLE transcripts. All NIHCOLE isoforms are presented and aligned to the upstream part of the genomic NIHCOLE region. The donor (D) and acceptor (A) parts of P12 are also annotated. Exons 1-3 are annotated to enable comparison to Figure 1. Figure 5b shows the design of the primers and probes to detect NIHCOLE transcripts focusing on one isoform (NIHCOLE-204 is used here as example), and highlighting the location of P12-R0X probe used for quantitative detection of P12 junction. The donor (D) and acceptor (A) parts of P12 junction are highlighted. Figure 5c Experimental strategy for MN0-P12 amplification by single cell RT-PCR. d. Schematic representation of two sets of primers on exons 2 and 3 of Pl 2 for Pl 2 amplification during PCR1 and PCR2, based on a nested design. Table with expected Pl 2 gDNA and cDNA sizes after amplification at PCR1 and PCR2. e. Validation of P12 amplification by gel electrophoresis. Expected P12 cDNA and gDNA (genomic DNA) bands are indicated with an arrow.Figure 6. Figure 6a shows the list of lungs, colorectal (COAD), brain, ovary (OV), and pancreatic (PAAD) cell lines positive (Pl 2+) or negative (Pl 2-) for MN0-P12, as measured by quantitative PCR. Figure 6b shows P12 expression in positive and negative cell lines measured by digital PCR. Figure 6c shows Pl 2 expression in positive and negative cell lines, and primary blood mononuclear cells (MNT-218, MNT-219). Figure 6d shows the RNA expression profile of P12 splicing junction in bulk RNA seq of healthy lungs, juxta tumors and lung tumors, in particular lung adenocarcinoma (LU AD) and lung squamous cell carcinoma (LUSC) cohorts. Each dot is a sample and mean of all samples is represented. Figure 6e shows Pl 2 expression normalized to housekeeping gene P0LR2A, measured by quantitative RT-qPCR, between healthy lung (n=5), LUAD (n=8) and LUSC (n=9) tumors. Samples showing no P12 amplification by RT-qPCR were set to zero. Figure 6f shows P12 expression normalized to housekeeping gene GADD45, measured by digital PCR in the same samples. For b) and c), mean of biological replicates is represented, and conditions were compared using Kruskal-Wallis statistical tests combined with a Dunn’s post-hoc. ns, not significant; *p < 0.05; **p < 0.01. Figure 6 g) And h) show P12 expression normalized to housekeeping gene P0LR2A, measured by quantitative PCR, between primary tumors and pairednon-tumoral tissue (NAT) (n=5) . Samples showing no P12 amplification by qPCR were set to zero. STAD= Stomach adenocarcinoma, COAD= Colon adenocarcinoma.Figure 7. Figure 7a shows the design of FISH probes (high-level and genomic representation). All NIHCOLE isoforms which contain the first five exons, are presented and aligned to the genomic NIHCOLE region. The location of the 12 ZZ pairs comprising the probe is depicted in the corresponding exon. Figure 7b shows the design of probes with zoom-in of the region of the NIHCOLE transcripts containing the first three exons (cDNA representation of an example isoform NIHCOLE-203). Figure 7c-h show NIHCOLE transcript expression in cell lines evaluated with FISH and compared to qPCR. Figure 7(c) shows the number of dots (equivalent to transcripts per cell evaluated with the 12 ZZ probes in A172 (n=77 cells), LN229 (n=85 cells), SK-MES-1 (n=103 cells), NCI-H446 (n=24 cells). Figure 7(d) shows the coverage (percentage of positive cells) for each of the cell lines indicated in a. Figure (e) shows a representative plot of qPCR for the same cell lines; P12 splicing junction expression normalized to housekeeping gene P0LR2A Figures 7(g-h) are similar to Figures 7c-e, with analyses performed on tissue samples from LU AD and LUSC.Figure 8. Figure 8 A shows the workflow of screening and reformatting of P12 / HLA targeting scFv clones. Figure 8b shows the schematic of the selection approach for cross-reactive peptides.Figure 9. Figure 9a shows the structure of a tandem scFv (or BiTE) attached to the TCR. Figure 9b shows the serial process of plating, transducing producer cells (e.g., HEK293 or T cells), and generating BiTEs in the supernatant that can redirect T cell cytotoxicity. Using a different BiTE construct per well allows for rapid parallel screening in similar conditions.Figure 10. Figure 10a shows the structure of a CD28-CD3(j-IXX CAR. Figure 10b shows a schematic of the CAR-T production protocol. Figure 10c shows the serial process of plating, transfecting vector particle cells, transducing T cells with viral particles, and harvesting CAR T cells for analysis and downstream functional assays.Figure 11. Figure Ila shows the expression of CAR at the plasma membrane (left panel) and the binding of MNO-P12 / HLA-A*03 specific CAR T cells to tetramers (right panel), measured by flow cytometry. Figure 11b shows alanine scan analysis, measured by flow cytometry with peptide-loaded A*03 tetramers. Figure 11c shows the binding of MNO-P12 / HLA-A*03 tetramer and XR peptide / HLA-A*03 tetramers to T cells expressing a highly MNO-P12 / HLA-A*03-specific CAR (upper panel) or a less specific, cross-reactive CAR (lower panel), measured by flow cytometry. Figure lid shows the specific lysis of CAR-Ts specific for MN0-P12 presented on HLA-A*03 against LN229-GFP-Luc (HLA-A3pos) cells. Untransduced T cells were used as a negative control. Cytotoxicity was measured by bioluminescence at 24h for the four top binders.Figure lie: LN229-GFP-Luc cell growth was followed during 7 days by cell impedance measurement revealing cytotoxicity of binder 9 (at 1:2 and 1:10 Effector: Target ratio). Untransduced T cells and tumor cells alone were used as negative control. CAR-T cells targeting a peptide expressed by LN229 cells were used as positive control.Figure 12: shows the design of gRNAs used in knock-out approaches and primers used in DNA amplifications by PCR.DETAILED DESCRIPTIONDefinitionsUnless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0105] As used herein, the term “comprising” also specifically includes embodiments “consisting of and “consisting essentially of the recited elements, unless specifically indicated otherwise.The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).As used herein a “nucleotide” is a molecule that contains a base moiety, a sugar moiety and a phosphate moiety. Nucleotides can be linked together through their phosphate moieties and sugar moieties creating an intemucleoside linkage. The base moiety of a nucleotide can be adenin-9-yl (A), cytosin-l-yl (C), guanin-9-yl (G), uracil- 1-yl (U), and thymin-l-yl (T). The sugar moiety of nucleotide is a ribose or a deoxyribose. The phosphate moiety of nucleotide is pentavalentphosphate. A non-limiting example of a nucleotide would be 3 '-AMP (3 '-adenosine monophosphate) or 5'-GMP (5 '-guanosine monophosphate). There are many varieties of these types of molecules available in the art and available herein.A “nucleotide analog” as used herein is a nucleotide which contains some type of modification to either the base, sugar, or phosphate moieties. Modifications to nucleotides are well known in the art and would include for example, 5 -methylcytosine (5-me-C), 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, and 2-aminoadenine as well as modifications at the sugar or phosphate moieties. There are many varieties of these types of molecules available in the art and available herein. “Nucleotide substitutes” as used herein are molecules having similar functional properties to nucleotides, but which do not contain a phosphate moiety, such as peptide nucleic acid (PNA). Nucleotide substitutes are molecules that will recognize nucleic acids in a Watson-Crick or Hoogsteen manner, but which are linked together through a moiety other than a phosphate moiety. Nucleotide substitutes are able to conform to a double helix type structure when interacting with the appropriate target nucleic acid. There are many varieties of these types of molecules available in the art and available herein.It is also possible to link other types of molecules (conjugates) to nucleotides or nucleotide analogs to enhance for example, cellular uptake. Conjugates can be chemically linked to the nucleotide or nucleotide analogs. Such conjugates include but are not limited to lipid moieties such as cholesterol moiety. (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556). There are many varieties of these types of molecules available in the art and available herein.A “Watson-Crick interaction” referred to at least one interaction with the Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute. The Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute includes the C2, Nl, and C6 positions of a purine-based nucleotide, nucleotide analog, or nucleotide substitute and the C2, N3, C4 positions of a pyrimidine-based nucleotide, nucleotide analog, or nucleotide substitute.A “Hoogsteen interaction” means the interaction that takes place on the Hoogsteen face of a nucleotide or nucleotide analog, which is exposed in the major groove of duplex DNA. The Hoogsteen face includes the N7 position and reactive groups (NH2 or 0) at the C6 position of purine nucleotides.As used herein, the terms "polynucleotide" or “nucleic acid” refers both to a polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). A polynucleotide is made up of four bases; adenine, cytosine, guanine, and thymine / uracil (uracil is used in RNA). A coding sequence from a nucleic acid is indicative of the sequence of the protein encoded by the nucleic acid.The terms “recombinant or synthetic nucleic acid (r / sNA) molecules” relates to nucleic acid molecules that are constructed outside of living cells. They are made by joining DNA or RNA segments (natural or synthetic) to DNA or RNA molecules that can replicate within a living cell. They may also result from replication of previously constructed recombinant molecules.The term “complementarity” or “complementary” with respect to oligonucleotide therapeutic agents refers to the capacity of base pairing, or hybridization, between the nucleobases of a first nucleic acid strand and the nucleobases of a second nucleic acid strand, mediated by hydrogen binding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between corresponding nucleobases. The ability of the first and second nucleic acid strands to hybridize may be evaluated by the number of matches or mismatches between paired bases. For example, in DNA, adenine (A) matches / is complementary to thymine (T); and guanosine (G) is complementary to cytosine (C). For example, in RNA, adenine (A) is complementary to uracil (U); and guanosine (G) is complementary to cytosine (C). Some bases, e.g. inosine, are considered universal bases that pair with any other base. In certain embodiments, complementary nucleobase means a nucleobase of an antisense oligonucleotide that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of antisense oligonucleotide is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair. Nucleobases comprising certain modifications may maintain the ability to pair with a counterpart nucleobase and thus, are still capable of nucleobase complementarity. Alternatively, the ability of the first and second nucleic acid strands to hybridize may be evaluated under stringent conditions such as 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70°C for 12- 16 hours followed by washing (see, e.g., "Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Non-Watson-Crick base pairing can also occur through other hydrogen bond interactions, or interactions between C-H and O / N groups, such as Hoogsteen A:U and GU wobble pairs. The first and second nucleic acid strands may hybridize sufficiently to each other to modulate expression when they are less than 100% complementarity. Thus, complementary as used herein includes base pairing that is 100% complementary, or about 95%, about 90%, about 85%, about 80%, about 75%, or about 70% complementary, as long as it is sufficient to modulate gene expression.Nucleic acids can hybridize to other nucleic acids under particular hybridization conditions. Methods for hybridizing nucleic acids are well known in the art. See, e.g., Current Protocols in Molecular Biology, John Wiley and Sons, N.Y. (1989), incorporated by reference, 6.3.1-6.3.6. As defined herein, a moderately stringent hybridization condition uses for example a prewashing solution containing 5x sodium chloride / sodium citrate (SSC), 0.5% SDS, 1.0 mM EDTA (pH 8.0),hybridization buffer of about 50% formamide, 6xSSC, and a hybridization temperature of 55° C. (or other similar hybridization solutions, such as one containing about 50% formamide, with a hybridization temperature of 42° C), and washing conditions of 60° C. in 0.5xSSC, 0.1% SDS. A stringent hybridization condition hybridizes for example in 6xSSC at 45° C., followed by one or more washes in O.lxSSC, 0.2% SDS at 68° C. Furthermore, one of skill in the art can manipulate the hybridization and / or washing conditions to increase or decrease the stringency of hybridization such that nucleic acids comprising nucleotide sequence that are at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to each other typically remain hybridized to each other. The parameters affecting the choice of hybridization conditions and guidance for devising suitable conditions are set forth by, for example, Sambrook, Fritsch, and Maniatis (Molecular Cloning: A Faboratory Manual, Cold Spring Harbor Faboratory Press, Cold Spring Harbor, N.Y., chapters 9 and 11 (1989); Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley and Sons, Inc., sections 2.10 and 6.3-6.4 (1995), both of which are herein incorporated by reference in their entirety for all purposes) and can be readily determined by those having ordinary skill in the art based on, for example, the length and / or base composition of the DNA.Genome assembly refers to the reconstruction of the whole genome sequence by aligning and merging sequence reads generated from the current genome sequencing technologies. Sequence assembly is one of the basic steps after performing next generation sequencing (NGS) such as e.g. PacBio SMRT sequencing, or Nanopore sequencing that mostly generate short DNA read lengths (25-400 bp depending on the NGS platform). Genome assembly programs typically use the data from single and paired reads to assemble a genome. Single reads are continuous sequenced fragments that can be joined up through overlapping regions into “contigs”. Paired reads are the two ends of the same DNA molecule, which come from sequencing one end of DNA and then sequencing it from the other end. Paired-read data can indicate the size of repetitive regions. The established genome assembly can be submitted to annotated databases such as the UCSC Known Genes dataset (based on protein data from Swiss-Prot / TrEMBL (UniProt) and the associated mRNA data from GenBank - see Hsu F et al. The UCSC known genes. Bioinformatics. 2006,22(9): 1036- 46), The NCBI Reference sequences (RefSeq - see Pruitt KD, et al. NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 2007;35(Database):D61-5), and Ensembl Genomes (Flicek P et al. Ensembl 2014. Nucleic Acids Res. 2014;42(Database issue) :D749-55). GRCh38.pl4 (GCA_000001405.29 / GCF_000001405.40), the latest update to the human reference assembly has been released in May 2022 by the Genome Reference Consortium. Prior version GRCh37 (also known as HG19) had been released in 2009 and remain available such as in as a stable archive. Tools for conversion of annotation are also available.A “reading frame” (RF), as used in genomic and intended herein, is a way of dividing the sequence of nucleotides in a nucleic acid (DNA or RNA) molecule into a set of consecutive, non-overlapping triplets. As intended herein, a transcript comprises 3 reading frames. A transcript coding for a peptide therefore means herein that a reading frame of the said transcript can be translated in the said peptide.An “Open Reading Frame” (ORF) as herein intended can be represented as a portion of a DNA sequence containing non-overlapping triplets or codons and that is bounded by stop codons. As intended herein, a transcript can comprise one or more ORFs.A “canonical ORF” as herein intended is typically a protein coding sequence with specified reading frame within a mRNA sequence which is described or annotated in annotated genome assemblies such as for example RefSeq, Ensembl, etc. Typically, a canonical ORF is the annotated (in reference databases) ORF of a given exon in normal healthy cells.A “non-canonical ORF” as herein intended is a coding sequence with specified reading frame within a mRNA sequence which is not described (i.e. unannotated) in genome databases (e.g. Ensembl). For example, non-canonical ORFs include shifted reading frames (as compared to canonical reading frame), chimeric ORFs, or ORFs originating from the dark genome (e.g. non-coding DNA regions such as for example regions coding for IncRNAs, TE, or UTR regions).As used herein, a CDS refers to a contiguous sequence which begins with, and includes, a start codon and ends with, and includes, a stop codon. The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for a protein.As used herein, an " Exon” refers to a region of the transcript sequence within a gene which is not removed from the primary RNA transcript by RNA splicing. An “exon” is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. In RNA splicing, introns are removed, and exons are covalently joined to one another as part of generating the mature RNA. In protein-coding genes, the exons include both the protein-coding sequence and the 5'- and 3 '-untranslated regions (UTR). The first exon generally includes both the 5'-UTR and the first part of the coding sequence, although exons containing only regions of 5'-UTR or (more rarely) 3'-UTR can occur in some genes. Some non-coding RNA transcripts also have exons and introns. The entire set of exons of an individual constitutes the exome.As used herein, an untranslated region (UTR) refers to either of two sections, one on each side of a coding sequence (CDS) on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR (or leader sequence), or if it is found on the 3' side, it is called the 3' UTR (or trailer sequence).Long non-coding RNAs (long ncRNAs, IncRNA) are a type of RNA, generally defined as transcripts of more than 200 nucleotides that are not translated into protein. Long non-coding RNAs include intergenic lincRNAs, intronic ncRNAs, as well as sense and antisense IncRNAs.A « pseudogene » is a segment of DNA that structurally resembles a gene but is not capable of coding for a protein. Pseudogenes are most often derived from genes that have lost their proteincoding ability due to accumulated mutations that have occurred over the course of evolution. The term transcriptome refers to the total RNA, whether from a single cell or a population of cells. It can also refer to the total mRNA, with a focus on gene expression and what is being specifically coded for proteins.A transcript is a single-stranded RNA molecule that is produced from a DNA template through the process of transcription. It typically refers to a contiguous RNA sequence (or isoform) inferred from RNA-Seq data with or without using a reference genome. These transcripts are computationally assembled from RNA (short or long reads). Transcripts according to the present disclosure can be derived from coding region of the genome (i.e. exonic sequences of a gene) and / or non coding regions of the genome (including introns, transposable elements, 3’UTR regions, 5’UTR regions, or non canonical RNAs such a lncRNA)s. Transcripts therefore includes include in a non-limitative manner splicing isoforms (including alternative, non canonical and / or non annotated variants), IncRNAs transcripts and fusion transcripts.RNA-Seq methods are based on NGS (next generation sequencing) methods and generally comprise the following steps: the standard workflow begins in the laboratory, with RNA extraction, followed by mRNA enrichment or ribosomal RNA depletion, cDNA synthesis and preparation of an adaptor-ligated sequencing library. The library is then sequenced to a read depth of about 10-30 million reads per sample on a high-throughput platform (such as for example the Illumina GA / HiSeq - see http: / / www.illumina.com -, SOLiD or Roche 454). The final steps are computational: aligning and / or assembling the sequencing reads to a transcriptome, quantifying reads that overlap transcripts, filtering and normalizing between samples, and statistical modelling of significant changes in the expression levels of individual genes and / or transcripts between sample groups. The review of Stark, R., Grzelak, M. & Hadfield, J. RNA sequencing: the teenage years. Nat Rev Genet 20, 631-656 (2019); provides a recent overview and comparison of broadly used short readRNAseq platforms as well as for examples of computational tools for sequence alignments (e.g. TopHat, STAR or HITSAT2), quantification (HTseq, featureCounts, etc.). RNA seq data can be issued from bulk tissues and / or cells as well as from single cell analysis. An RNA read is a sequence obtained from a single sequencing experiment. An aligned read, is a sequence that has been aligned to a common reference genome. Typically these reads can range from hundreds of thousands to tens of millions.Recently long read sequencing (LRS) have been developed and include notably the SMRT sequencing by PacBio and the nanopore sequencing by ONT (see for review Mantere, Tuomo et al. “Long-Read Sequencing Emerging in Medical Genetics.” Frontiers in geneticsvol. 10426. 7 May.2019 and Warburton, Peter E, and Robert P Sebra. “Long-Read DNA Sequencing: Recent Advances and Remaining Challenges.” Annual review of genomics and human genetics vol. 24 (2023): 109-132). The predominant difference between LRS and the conventional short read (SR)-NGS approaches is the significant increase in read length. In contrast to short reads (about 150-300 bp), LRS has the capacity to sequence on average over 10 kb in one single read, thereby requiring less reads to cover the same gene or transcript.The MHC ligandome refers to the complete set of peptides that are bound and presented by Major Histocompatibility Complex (MHC) molecules on the surface of cells. These peptides, also called MHC-associated peptides or immunopeptidomes, play a critical role in immune surveillance and T-cell recognition. MHC -I ligandome are peptides typically derived from intracellular proteins that are bound and presented by MHC class I molecules.A “transposable element” (TE) is to be understood as both class I (retrotransposons, including those containing LTRs, LINEs and SINEs) and class II (DNA transposons) endogenously part of the genome (i.e.: not from infection). This includes both autonomous and non-autonomous elements from both classes. According to the present disclosure the TE sequences can be for example selected from TE of class I, such as retrotransposons including Endogenous RetroVirus (ERVs), Long interspersed nuclear elements (LINEs) and short interspersed nuclear element (SINEs) and mammalian long terminal repeat transposon (MaLR), and TE of class II, such as DNA transposons endogenously part of the genome.The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (he; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).The terms "peptide”, “polypeptide" or “proteins” are used herein interchangeably to designate a sequence of amino acid residues, typically L-amino acids, connected to each other, typically by peptide bonds between the a-amino and carboxyl groups of adjacent amino acids (that is a polymer of amino acid residues of any length). The polymer can be linear or branched, it may comprise modified amino acids or amino acid analogs, and it may be interrupted by chemical moieties other than amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation,acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling or bioactive component. A polypeptide may be of various length; in neutral form (uncharged) or in the form of a salt; and either free of modifications such as glycosylation, side chain oxidation, or phosphorylation or containing these modifications, providing that the modification does not impair the biological activity of the polypeptides as herein described. The term polypeptide includes a protein which refers to the product of a gene or any fragment or variant derived from said protein. The term “variant” with respect to an amino acid sequence refers to a functional variant which retains the activity of the native sequence.A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution an amino acid with a chemically or functionally similar amino acid. Examples of conservative substitution tables providing similar amino acids are well known in the art. Conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antigen binding protein (ABP) generated by making one or more conservative substitutions of amino acid residues in a parent ABP is referred to as a “conservatively modified variant.”Recombinant proteins or polypeptides are typically produced from cloned genes by recombinant nucleic acid techniques, generally in a heterologous expression system. The process begins with DNA or RNA fragments containing the nucleic acid of interest. Once it is identified, isolated, and characterized, that gene is inserted into a vector by recombinant nucleic acid technology. These vectors are then inserted into a host cell or a target cell and have the ability to be expression using the host / target cell machinery.As used herein, the identity / similarity between two or more nucleic acid sequences, or two or more amino acid sequences, is expressed in terms of the identity or similarity between the sequences. Sequence identity can be measured in terms of percentage identity; the higher the percentage, the more identical the sequences are. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i. e., % identity = number of identical positions / total number of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. Similarly, sequence similarity can be measured in terms of percentage identity or similarity (which takes into account conservative amino acid substitutions); the higher the percentage, the more similar the sequences are. Polypeptides or protein domains thereof that have a significant amount of sequence identity and also function the same or similarly to one another (for example, proteins that serve the same functions in different species or mutant forms of a protein that do not change the function of the protein or the magnitude thereof) can be called "homologs."Methods of alignment of sequences for comparison are well known in art such as BLAST (Altschul et al., J. Mol. Biol., 1990, 215, 403-), FASTA or CLUSTALW. Various programs and alignment algorithms are described in: Smith & Waterman, Adv Appl Math 2, 482 (1981); Needleman & Wunsch, J Mol Biol 48, 443 (1970); Pearson & Lipman, Proc Natl Acad Sci USA 85, 2444 (1988); Higgins & Sharp, Gene 73, 237-244 (1988); Higgins & Sharp, CABIOS 5, 151-153 (1989); Corpet etai, Nuc Acids Res 16, 10881-10890 (1988); Huang etai, Computer App Biosci 8, 155-165 (1992); and Pearson et al, Meth Mol Bio 24, 307-331 (1994). In addition, Altschul et al., J Mol Biol 215, 403-410 (1990), presents a detailed consideration of sequence alignment methods and homology calculations.The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al. (1990), supra) is available from several sources, including the National Center for Biological Information (NCBI, National Library of Medicine, Building 38A, Room 8N805, Bethesda, MD 20894) and on the Internet, for use in connection with the sequence analysis programs blastp, blastn, blastx, tblastn and tblastx. Additional information can be found at the NCBI web site.BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. If the two compared sequences share homology, then the designated output file will present those regions of homology as aligned sequences. If the two compared sequences do not share homology, then the designated output file will not present aligned sequences.Once aligned, the number of matches is determined by counting the number of positions where an identical nucleotide or amino acid residue is presented in both sequences. The percent sequence identity is determined by dividing the number of matches either by the length of the sequence set forth in the identified sequence, or by an articulated length (such as 100 consecutive nucleotides or amino acid residues from a sequence set forth in an identified sequence), followed by multiplying the resulting value by 100. For example, a nucleic acid sequence that has 1166 matches when aligned with a test sequence having 1154 nucleotides is 75.0 percent identical to the test sequence (1166=1554*100=75.0). The percent sequence identity value is rounded to the nearest tenth. For example, 75.11, 75.12, 75.13, and 75.14 are rounded down to 75.1, while 75.15, 75.16, 75.17, 75.18, and 75.19 are rounded up to 75.2. The length value will always be an integer. In another example, a target sequence containing a 20- nucleotide region that aligns with 20 consecutive nucleotides from an identified sequence as follows contains a region that shares 75 percent sequence identity to that identified sequence (that is, 15=20*100=75).For comparisons of amino acid sequences of greater than 30 amino acids, the Blast 2 sequences function is employed using the default BLOSUM62 matrix set to default parameters, (gap existence cost of 11, and a per residue gap cost of 1). Homologs are typically characterized by possession of at least 70% sequence identity counted over the full-length alignment with an amino acid sequenceusing the NCBI Basic Blast 2.0, gapped blastp with databases such as the nr database, swissprot database, and patented sequences database. Queries searched with the blastn program are fdtered with DUST (Hancock & Armstrong, Comput Appl Biosci 10, 67-70 (1994.) Other programs use SEG. In addition, a manual alignment can be performed. Proteins with even greater similarity will show increasing percentage identities when assessed by this method, such as at least about 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to a protein.When aligning short peptides (fewer than around 30 amino acids), the alignment is performed using the Blast 2 sequences function, employing the PAM30 matrix set to default parameters (open gap 9, extension gap 1 penalties). Proteins with even greater similarity to the reference sequence will show increasing percentage identities when assessed by this method, such as at least about 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to a protein. When less than the entire sequence is being compared for sequence identity, homologs will typically possess at least 75% sequence identity over short windows of 10-20 amino acids, and can possess sequence identities of at least 85%, 90%, 95% or 98% depending on their identity to the reference sequence. Methods for determining sequence identity over such short windows are described at the NCBI web site.One indication that two nucleic acid molecules are closely related is that the two molecules hybridize to each other under stringent conditions, as described above. Nucleic acid sequences that do not show a high degree of identity may nevertheless encode identical or similar (conserved) amino acid sequences, due to the degeneracy of the genetic code. Changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid molecules that all encode substantially the same protein. Such homologous nucleic acid sequences can, for example, possess at least about 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% sequence identity to a nucleic acid that encodes a protein."Isolated", as used herein, refers to a peptide or nucleic molecule separated from other components that are present in the natural environment of the molecule or a naturally occurring source macromolecule (e.g., including other nucleic acids, proteins, lipids, sugars, etc.)."Synthetic", as used herein, refers to a peptide or nucleic molecule that is not isolated from its natural sources, e.g., which is produced through recombinant technology or using chemical synthesis.The major histocompatibility complex (MHC) system is a complex of genes encoding glycoproteins (including cell-surface proteins) responsible for the regulation of the immune system found in many animals. The human version of the MHC is named human leucocyte antigen (HLA); however it must be noted that both the terms HLA and MHC are used herein interchangeably in the absence ofprecision. The human MHC genes are located on chromosome 6 and encompasses the A, B, C, DP, DQ, DR, C4, Bf, and C2 regions and form a closely linked cluster of genes. The MHC gene family produces various glycoproteins. Based on their distinct structural and functional characteristics, MHC genes can be classified into three separate gene subfamilies: class I, class II, and class III. Major histocompatibility complex (MHC) class I (MHC I) and class II (MHCII) proteins play a pivotal role in the adaptive branch of the immune system. Both classes of proteins share the task of presenting peptides on the cell surface for recognition by T cells. MHC complexes class I and class II share an overall similar fold. The binding platform is composed of two domains, originating from a single heavy a-chain in the case of MHC class I and from two chains in the case of MHC II (a-chain and P-chain). Two membrane-proximal immunoglobulin (Ig) domains support the peptide-binding unit. One Ig domain is present in each chain of MHC II, while the second Ig-type domain of MHC I is provided by non-covalent association of the invariant light chain beta-2 microglobulin ( 2in) with the a-chain. Transmembrane helices anchor the a-chain of MHC I and both chains of MHC II in the membrane. In MHC class I molecules, the two heterodimeric polypeptide chains (the a-chain and the P-2 microglobulin) establish a noncovalent bond via their shared three domains. The a-chain generally comprises a 1 and a 2 domains which form a groove for presenting an HLA-restricted peptide, and an a plasma membrane- spanning domain which interacts with the CD8 coreceptor of T-cells. The a-chain is encoded through numerous highly polymorphic genes, whereas the P-2 microglobulin subunit is encoded by fewer non-polymorphic genes. When the 1st and 2nd domains are folded together, they form a basket-like groove into which antigenic peptides can bind. Typically, this groove or basket is made up of eight to eleven amino acids.Class I MHC-restricted peptides (also referred to interchangeably herein as HLA-restricted antigens, HLA-restricted peptides, antigenic peptides, MHC-restricted antigens, MHC associated peptides or MAP, MHC peptides, or pMHC) generally bind to the heavy chain alphal-alpha2 groove via about two or three anchor residues that interact with corresponding binding pockets in the MHC molecule. The beta-2 microglobulin chain plays an important role in MHC class I intracellular transport, peptide binding, and conformational stability.MHC-associated peptide therefore refers herein to a peptide that is able to specifically bind to (and form a molecular complex with) an MHC molecule. MHC type I associated peptides typically comprise between 8-11 amino acid residues. Different HLA-I alleles have distinct binding specificities, which implies that a broad spectrum of peptides can be displayed across different individuals. Most peptides bound to MHC class I molecules are derived from the degradation of intracellular proteins by the proteasome; these peptides are pumped into the endoplasmic reticulum (ER) by the TAP transporter, where they can be further processed and loaded onto MHC class I.Peptide ligands for MHC class I can also be derived from lysosomal protein degradation and through the action of proteases in the cytosol or ER.ELLA type I molecules are expressed in virtually all nucleated cells. HLA-I proteins are primarily encoded by three genes (HLA-A, HLA-B, and HLA-C), which are widely expressed in most cell types in human. In addition, specialized cell types can express HLA-E, HLA-F, or HLA-G genes. HLA-A, -B, and -C genes are the most polymorphic genes in the human genome with more than 12,000 distinct alleles described in the human population. Humans have in general different combinations of HLA-I alleles and, therefore, express up to six different HLA-I proteins (two for each gene). The HLA-A and -B molecules are predominantly involved in antigen presentation to T cells. In humans, HLA-A and -B allotypes are grouped into supertypes based on similarity in their peptide-binding profdes, and six HLA-A (A01, A01A03, A01A24, A02, A03, and A24) and six HLA-B (B07, B08, B27, B44, B58, and B62) supertypes can be distinguished. Details on the main HLA supertypes and alleles can be found in the following reviews: Sidney, J., Peters, B., Frahm, N. et al. “HLA class I supertypes: a revised and updated classification BMC Immunol 9, 1 (2008); and Sanchez-Mazas, A., Nunes, J. M., & PGAE HLA Consortium of the 18th International HLA and Immunogenetics Workshop (2024). “The most frequent HLA alleles around the world: A fundamental synopsis. Best practice & research”, the content of which is included herein by reference.HLA-II proteins are encoded by several genes (HLA-DRA, HLA-DRB1,3,4,5, HLA-DPA1, HLA- DPB1, HLA-DQA1, HLA-DQB1) and also show a very high level of polymorphism in the humans (except for HLA-DRA). HLA-II form heterodimers (HLA-DRA / HLA-DRB1,3,4,5; HLA- DPA1 / HLA-DPB1 and HLA-DQA1 / HLA-DQB1). These dimers bind longer peptides (12-20 amino acids) within an open-ended peptide-binding site. In the class II pathway, peptides coming from the degradation of phagocytosed extracellular proteins as well as endogenous proteins degraded through autophagy are presented on HLA-II molecules for recognition by immune cells (e.g CD4 T cells). Unlike HLA-I, HLA-II molecules are mainly expressed on specific professional antigen-presenting cells (pAPCs) such as dendritic cells or B cells, as well as by some cancer cells (such as melanoma). pAPCs can also uptake exogenous antigens and present them on HLA-I. This process is called cross-presentation, and it is crucial for priming of naive T cells.Further details on MHC7HLA complexes, see “Immunobiology: The Immune System in Health and Disease”. 5th edition. Janeway C A Jr, Travers P, Walport M, et al. New York: Garland Science; 2001; as well as Wieczorek M et al. “Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation”. Front Immunol 2017;8:292); Zhang, S., & Li, J. (2023). Molecular Characteristics, Functional Definitions, and Regulatory Mechanisms for Cross-Presentation Mediated by the Major HistocompatibilityComplex: A Comprehensive Review. International journal of molecular sciences, 25(1), 196); as well as Duan Z, Ho M. T-Cell Receptor Mimic Antibodies for Cancer Immunotherapy. Mol Cancer Ther. 2021; 20(9): 1533-1541. doi: 10.1158 / 1535-7163.MCT-21-0115.“Antigen presenting cells” (APC) can be cells which present peptide fragments of protein antigens (MAP) in association with MHC molecules on their cell surface. Some APCs may activate antigen specific T cells. Professional antigen-presenting cells are very efficient at internalizing antigen, either by phagocytosis or by receptor-mediated endocytosis, and then displaying a fragment of the antigen, bound to a class II MHC molecule, on their membrane. The T cell recognizes and interacts with the antigen-class II MHC molecule complex on the membrane of the antigen presenting cell. An additional co-stimulatory signal is then produced by the antigen presenting cell, leading to activation of the T cell. The expression of co-stimulatory molecules is a defining feature of professional antigen-presenting cells. The main types of professional antigen-presenting cells are dendritic cells, which have the broadest range of antigen presentation, and are probably the most important antigen presenting cells, macrophages, B-cells, and certain activated epithelial cells. Dendritic cells (DCs) are leukocyte populations that present antigens captured in peripheral tissues to T cells via both MHC class II and I antigen presentation pathways. It is well known that dendritic cells are potent inducers of immune responses and the activation of these cells is a critical step for the induction of antitumoral immunity. Dendritic cells are conveniently categorized as “immature” and “mature” cells, which can be used as a simple way to discriminate between two well characterized phenotypes. However, this nomenclature should not be construed to exclude all possible intermediate stages of differentiation. Immature dendritic cells are characterized as antigen presenting cells with a high capacity for antigen uptake and processing, which correlates with the high expression of Fc receptor (FcR) and mannose receptor. The mature phenotype is typically characterized by a lower expression of these markers, but a high expression of cell surface molecules responsible for T cell activation such as class I and class II MHC, adhesion molecules (e.g., CD54 and CD11) and costimulatory molecules (e.g, CD40, CD80, CD86 and 4-1 BB). As used herein, the terms "antigen" or "immunogen" are used interchangeably to refer to a substance, typically a protein or a (poly)peptide, which is capable of inducing an immune response in a subject. The term also refers to proteins, polypeptides or peptides that are immunologically active in the sense that once administered to a subject (either directly or by administering to the subject a nucleotide sequence or vector that encodes the protein) is able to evoke a cell-mediated or humoral response, for example, cytotoxic T lymphocyte (CTL (e.g., CD8+)), helper T lymphocyte (Th (e.g., CD4+)) and / or B lymphocyte antibody response. Antigens typically include viral antigens, fungal antigens, bacterial antigens, self-antigens (also named autoantigens), and tumor antigens. Typically, antigens according to the present disclosure include antigens that are expressedin the context of a tumor (tumor antigens), an infectious disease (e.g. viral antigens), inflammatory and auto-immune diseases. In the present application the term “antigen” also refers to MHC-associated peptide (MAP) antigens in association with (i.e., complexed with or loaded to) an HLA (notably an HLA type I) molecule. Such molecular complex antigens are named interchangeably “HLA (or MHC)-PEPTIDE,” “pHLA(or MHC),” “peptide-HLA (or MHC),” and “peptide-HLA (or MHC) complexes”. In some embodiments, the terms “antigen” can also more broadly refers to polypeptides comprising one or more MHC type I epitope.The term “epitope” refers herein a portion of a polypeptide that can specifically binds to an antibody binding protein (ABP) or to an HLA molecule. An epitope that binds to an ABP (ABP epitope) may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Typically, an ABP epitope consists of surface-accessible amino acid residues and / or sugar side chains. In some embodiments, the epitope Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. In the context of a peptide-MHC complex, the epitope is formed both by the specific pMHC bounds the MHC molecule and the MHC molecule (notably the alpha helices that flank the peptide-binding groove). Such epitope can be recognized by a TCR and / or a TCR mimic binder.A “shared antigen” as used herein is an antigen that can be found among multiple patients, typically in a specific population (e.g., a specific population of cancer patients, such as a population of patients suffering from a cancer type or subtype).An epitope, notably an ABP epitope, can be determined using known techniques for epitope determination (see for details on the techniques of the art the following reviews: Hu, D., & Irving, A. T. (2023). “Massively-multiplexed epitope mapping techniques for viral antigen discovery”. Frontiers in immunology, 14, 1192385 and Nilvebrant, J., & Rockberg, J. (2018). An Introduction to Epitope Mapping. Methods in molecular biology (Clifton, N.J.), 1785, I 1 ) including (1) biochemical and molecular biology methods, such as peptide scanning, alanine scanning mutagenesis (see for example Weiss, G A et al. “Rapid mapping of protein functional epitopes by combinatorial alanine scanning.” Proceedings of the National Academy of Sciences of the United States of America vol. 97,16 (2000): 8950-4)) or site-directed mutagenesis; (2) competition assays (such as epitope Binning) as well as (3) biophysical techniques such as X-ray crystallography, cryoelectron microscopy (cryo-EM), or nuclear magnetic resonance (NMR) spectroscopy.The term “antigen binding protein” or “ABP” is used herein in its broadest sense and includes certain types of molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. In some embodiments, the ABP comprises an antibody. In someembodiments, the ABP consists of an antibody. In some embodiments, the ABP consists essentially of an antibody. An ABP specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, ABP fragments, and multi-specific antibodies. In some embodiments, the ABP comprises an alternative scaffold. In some embodiments, the ABP consists of an alternative scaffold. In some embodiments, the ABP consists essentially of an alternative scaffold. In some embodiments, the ABP comprises an antibody fragment. In some embodiments, the ABP consists of an antibody fragment. In some embodiments, the ABP consists essentially of an antibody fragment. In some embodiments, the ABP is a CAR, a TCR or a variant thereof.A “multi-specific ABP” is an ABP that comprises two or more different antigen- binding domains that collectively specifically bind two or more different epitopes. The two or more different epitopes may be epitopes on the same antigen (e.g, a single HLA-PEPTIDE molecule expressed by a cell) or on different antigens (e.g, different HLA-PEPTIDE molecules expressed by the same cell, or an HLA-PEPTIDE molecule and a non-HLA- PEPTIDE molecule). For example, multi-specific ABP can bind two (i.e, a “bispecific ABP”) or three (i.e, a “trispecific ABP”) different epitopes.A “monospecific ABP” is an ABP that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific ABP is a naturally occurring IgG molecule which, while divalent (i.e, having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. The binding specificity may be present in any suitable valency. An “immunoconjugate” is an ABP conjugated to one or more heterologous molecule(s), such as a therapeutic (cytokine, for example) or diagnostic agent.As used herein the term "antibody", or "immunoglobulin" have the same meaning, and are used equally in the present disclosure. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immuno-specifically binds an antigen.In natural antibodies (typically human antibodies), two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (1) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CHI, CH2 and CH3, collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer importantbiological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR).The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from nonhypervariable or framework regions (FR) can participate to the antibody binding site or influence the overall domain structure and hence the combining site. Complementarity Determining Regions or CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1 , L-CDR2, L- CDR3 and H-CDR1 , H-CDR2, H-CDR3, respectively. An antigen-binding site, therefore, typically includes six CDRs, comprising the CDRs set from each of a heavy and a light chain V region. Framework Regions (FRs) refer to amino acid sequences interposed between CDRs. Accordingly, the variable regions of the light and heavy chains typically comprise 4 framework regions and 3 CDRs of the following sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.The terms "Fc (fragment crystallizable) domain," "Fc portion," and "Fc region" refer to a C-terminal fragment of an antibody heavy chain, e.g., from about amino acid (aa) 230 to about aa 450 of human gamma heavy chain or its counterpart sequence in other types of antibody heavy chains (e.g., a, 8, s and p for human antibodies), or a naturally occurring allotype thereof. Unless otherwise specified, the commonly accepted Kabat amino acid numbering for immunoglobulins is used throughout this disclosure (see Kabat et al. (1991)) Sequences of Protein of Immunological Interest, 5th ed., United States Public Health Service, National Institute of Health, Bethesda, MD).“Fc effector functions” refer to those biological activities mediated by the Fc region of an ABP having an Fc region, which activities may vary depending on isotype. Examples of ABP effector functions include Clq binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate ABP-dependent cellular cytotoxicity (ADCC), and ABP dependent cellular phagocytosis (ADCP).Throughout the present description, amino acid sequences and the sequence position numbers used herein for the CHI and CL domains are defined according to Kabat et al, (Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.; 1991). The residues in antibody variable domains are conventionally numbered according to this system. An accurate Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” Kabatnumbered sequence. According to the Kabat numbering system, the CDRs of the heavy chain variable domain are typically located at residues 31-35 (H-CDR1), residues 50-65 (H-CDR2) and residues 95-102 (H-CDR3). Still according to the Kabat numbering system, the CDRs of the light chain variable domain are typically located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2) and residues 89-97 (L-CDR3). CDR sequences of binders 1-5 provided in the present application have been defined according to the Chothia (Chothia C, LeskAM. 1987, J Mol Biol 196, 901-917) andlMGT (IMGT system (LefrancMP etal. IMGT, the international ImMunoGeneTics database. Nucleic Acids Research (199) 27.1: 209- -212) numbering system.“Polyclonal antibodies” are antibodies that are secreted by different B cell lineages within the body. They are a collection of immunoglobulin molecules that react against a specific antigen, each identifying a different epitope (i.e.: the part of an antigen that is recognized by the binding domain of the immunoglobulin).“A monoclonal antibody” (mAb, more rarely called moAb) is an antibody produced from a cell lineage typically obtained by cloning a unique white blood cell. Monoclonal antibodies therefore share monovalent binding specificity and affinity for a particular epitope. The terms "monoclonal antibody" or "monoclonal antibody composition", as used herein, therefore refers to the preparation of antibody molecules of single molecular composition.An "isolated antibody", as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to an antigenic polypeptide as herein defined is substantially free of antibodies that specifically bind to other antigens than the said antigen). Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.“Affinity” refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an ABP or an HLA molecule) and its binding partner (also named herein a ligand or a target such as e.g., an antigen or more particularly an epitope or a peptide). Unless indicated otherwise, as used herein, “affinity” refers to the intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., an ABP and its binding antigen or epitope or an HLA molecule and its associated peptide or MAP (i.e.: MHC-associated peptide).The affinity of a binding molecule X for its binding partner Y can be represented by the dissociation equilibrium constant (Kd also written as KD or KD), which is used to evaluate and rank order strengths of bimolecular interactions. The binding of an antibody to its antigen is a reversible process, and the rate of the binding reaction is proportional to the concentrations of the reactants. At equilibrium, the rate of [binding molecule-target] complex formation is equal to the rate ofdissociation into its components [binding molecule] + [target]. The measurement of the reaction rate constants can be used to define an equilibrium or affinity constant (1 / Kd).The term "Kd", as used herein, is intended to refer to the equilibrium dissociation constant, a ratio of koff / kon, between the binding molecule and its target. The Kd represents the concentration of free ligand (target) required to occupy 50 % of the receptor (binding molecule) population at equilibrium and is expressed as a molar concentration (M).The term “Ka” (M'1), as used herein, refers to the association equilibrium constant of a particular binding molecule-target interaction. Ka= ka / kd.koff (or kd) the dissociation rate constant, represents the proportion of ligand (target) - receptor (binding molecule) complex that dissociates in unit time, in the absence of free ligand.kon(or ka) the association rate constant, describes the ligand (target) on rate at the receptor (binding molecule).Kd and affinity are inversely related such that, the smaller the Kd value (lower concentration), the greater the affinity of the binding molecule (e.g. antibody) for its target (e.g. antigen).Affinity may also be expressed as the inhibitory concentration 50 (IC50), that is the concentration at which 50% of the peptide is displaced. IC50 is the concentration of the tested peptide in a binding assay at which 50% inhibition of binding of a labeled reference peptide is observed. According to the conditions in which the assays are run (for example when assessing the binding of a given MHC-associated peptide (MAP) for an HLA molecule by using limiting HLA protein and labeled reference peptide concentrations), these values approximate Kd values.Specificity can further be assessed by determining EC50 values in binding experiments. As used herein, the parameter EC50 abbreviates for “half maximal effective concentration”. In a pharmacological context, this represents the concentration of a drug that is necessary to cause half of the maximum possible effect. In a binding assay, theEC50 is typically the concentration of ligand (i.e. non-labeled binding partner of the target, e.g. antigen) at which half of the target (e.g. label molecule, typically a fluorescent biomolecule, which binds to the ligand) is present in the bound state.Both the EC50 and the Kd can thus serve to quantify interactions and typically to compare the binding affinity of different antigens (e.g., primary antigen and off-targets antigens). Typically, the Kd Fit Model will yield a Kd while using the Hill Model will yield an EC50 value. The Hill fit is used for affinity quantification of multivalent interactions and provides information about the degree of Cooperativity. For monovalent interactions and interactions without cooperativity the Kd Fit Model is used instead. It is to be noted that the EC50, by definition, always depends on the targetconcentration. It is generally measured via the effect it induces, for example in cell-based assays, and typically allows the comparison of ligands measured in the same experimental setup.As used herein, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular target refers to the ability of a binding molecule to detectably bind its binding partner (also named a ligand or a target). Typically, a specific binding refers to the binding of a binding molecule (such as herein an HLA molecule or an ABP) to its binding partner (typically respectively a MAP or a target antigen) with a KD of 500 pM or less, notably 1 pM or less.As used herein the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective binding for” also mean that binding of the binding molecule (e.g. an HLA molecule or an ABP) for its specific (or selective) binding target (e.g., a MAP or an antigen) is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule) and typically refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologicals. Thus, under designated immunoassay conditions, the specified binding protein binds to a particular protein or peptide at least two times the background and more typically more than 10- to 100-times, notably between at least more than 10-to about 1000 times background.A selective binder shows little, or no cross-reactivity, meaning that it recognizes a given partner with much higher affinity than other partners. Cross-reactivity assays typically evaluate the potential for a given binding protein to recognize and bind to a competing target (e.g. an antigen) different to the one it was raised against and usually aim at identifying off-target binding. When such cross-reactivity cannot be detected, while giving a strong signal of the intended target at the same time and at the same antigen binding protein dilution, the binding protein is typically deemed selective.A binding protein (i.e. a binding molecule) that "cross-reacts with an antigen or other target" is usually intended to refer to a binding protein that binds that other target with a KDof 50 nM or less, notably of 10 nM or less, 1 nM or less, or 100 pM or less. A binding protein that "does not crossreact with a particular target" is usually intended to refer to a binding protein that binds to that particular target, with a Kd of 100 nM or greater, or a Kd of 1 pM or greater, or a Kd of 10 pM or greater. In certain embodiments, binding proteins that do not cross-react with the particular antigen exhibit essentially undetectable binding against this target in standard binding assays.A selective binding protein for a given target (e.g. an antigen) generally means that the said binding protein has about 10:1, about 20:1, about 50:1, about 100:1, 10.000:1 or greater ratio of affinityand / or avidity in binding to its specific target versus non-specific binding to other irrelevant molecules.In some embodiments, the term “cross-reactive binding” indicates that a peptide is bound by more than one HLA molecule; a synonym of which is degenerate binding. According to the present disclosure, “cross-reactive binding” may also indicate that the ABP binds a target antigen (e.g., the MHC peptide complex) and at least another (off-target) antigen within the same range of affinity. Preferred methods for determining the KD of binding proteins can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc, and Wiley Interscience, N. Y., 1992, 1993, and Muller, Meth Enzymol 1983, which references are entirely incorporated herein by reference. Affinity measurements are typically performed at 25°C.A well-known method for determining the KD of a binding molecule (such as an antibody) is by using surface plasmon resonance (SPR) (see Rich RL, Cannon MJ, Jenkins J, Pandian P, Sundaram S, Magyar R, et al. Extracting kinetic rate constants from surface plasmon resonance array systems. Anal Biochem. 2008; 373: 112 20 or Bravman T, Bronner V, NahsholO, Schreiber G. The ProteOn XPR36IM Array System — High Throughput Kinetic Binding Analysis of Biomolecular Interactions. Cellular and Molecular Bioengineering. 2008; 1:216- -28). A state-of-the-art high-throughput SPR platform is the Biacore® plastoform based on a biosensor system (see for detailed information regarding affinity assessment Rich RL, Day YS, Morton TA, Myszka DG. High-resolution and high-throughput protocols for measuring drug / human serum albumin interactions using BIACORE®. Anal Biochem. 2001 as well as Canziani GA, Klakamp S, Myszka DG. Kinetic screening of antibodies from crude hybridoma samples using biacore. Anal Biochem. 2004:325: 301 307). Example of KD measurement using surface plasmon resonance assays can be done such as with BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) at 25 °C with immobilized antigen CM5 chips at -10 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with A / -ethyl- / V-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and / V-hydroxysuccinimide (NHS) according to the supplier's instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg / ml (-0.2 pM) before injection at a flow rate of 5 pl / minute to achieve approximately 1 0 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25 °C at a flow rate of approximately 25 pl / min. Association rates (kon) and dissociation rates (kOff) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociationconstant (KD) is calculated as the ratio koff / kon(see, e.g., Chen et al. J. Mol. Biol. 293: 865- 881, 1999}. If the on-rate exceeds 106M'1s'1by the surface plasmon resonance assay above, then the on- rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm ; emission = 340 nm , 16 nm bandpass) at 25 °C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.Another high-throughput SPR platform is the Carterra LSA (Salt Lake City, UT). The Carterra LSA uses two microfluidic modules, a single flow cell (SFC) and a 96-channel printhead (96PH), which can be docked onto the chip surface via a user-defined choreography. It utilizes Surface Plasmon Resonance to detect binding interactions in real-time for up to 384 samples in parallel (see Brown, Michael E et al. “Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors. ” PloS one vol. 15,3 e0229206. 5 Mar. 2020).Another method for determining the KD of a binding molecule for its target involves the bio-layer interferometry (BLI) technology, on which the Octet® platform is based. The principle of BLI technology is based on the optical interference pattern of white light reflected from two surfaces - a layer of immobilized protein and an internal reference layer (BLI based instruments, such as ForteBio’s Octet RED384, generally allow quick evaluation of binding kinetics in a 96- or 384-well format). The binding between a ligand immobilized on the biosensor tip surface and an analyte in solution produces an increase in optical thickness at the biosensor tip, which results in a shift in the interference pattern measured in nanometers. The wavelength shift (AX) is a direct measure of the change in optical thickness of the biological layer, when this shift is measured over a period of time and its magnitude plotted as a function of time, a classic association / dissociation curve is obtained. This interaction is measured in real-time, allowing to monitor binding specificity, association rate and dissociation rate, and concentration (see notably Abdiche, Yasmina et al. “Determining kinetics and affinities of protein interactions using a parallel real-time label-free biosensor, the Octet. ” Analytical biochemistry vol. 377,2 (2008): 209-17, see also Concepcion J, Witte K, Wartchow C, Choo S, Yao D, Persson H, et al. Label-free detection of biomolecular interactions using BioLayer interferometry for kinetic characterization. Comb Chem High Throughput Screen. 2009; 12:791- 800).Other well-known methods to determine affinity and binding properties include (but are not limited to): ELISA (e.g. FriguetB, Chaffotte AF, Djavadi-Ohaniance L, Goldberg ME. Measurements of the true affinity constant in solution of antigen-antibody complexes by enzyme-linkedimmunosorbent-assay. J Immunol Met. 1985; 77: 305 319), western-blotting, Meso Scale Discovery (MSD) assays or Kinetic Exclusion Assays (KinExA) or equilibrium dialysis.Assays for determining binding characteristics are well known in the art and are described in detail, for example, in PCT publications WO 94 / 20127 and WO 94 / 03205, and other publications such Sidney et al., Current Protocols in Immunology 18.3.1 (1998); Sidney, et al., J. Immunol. 154:247 (1995); and Sette, et al., Mol. Immunol. 31:813 (1994). In some embodiments, binding can be expressed relative to binding by a reference standard peptide. For example, binding can be based on its IC50, relative to the IC50 of a reference standard peptide.Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the HLA molecule or the ABP to the target molecule is competitively inhibited by the control molecule.When used herein in the context of two or more binding molecules such as two different ABPs, or two different HLA molecules the term “competes with” or “cross-competes with” indicates that the two or more binding molecules compete for binding to a target. In classical competition assays, the target is bound on a solid support (e.g., a bead, well, membrane, tube, column, plate, sepharose, magnetic bead, cell, or chip) or expressed at the surface of a cell membrane and can be contacted with a binding molecule after which a second binding molecule is added. If the presence of the first binding molecule reduces binding of the second molecule, then the two binding molecules compete with each other.The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. This includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced, and the progeny of such cells. Host cells include “transformants” (or “transformed cells”) and “transfectants” (or “transfected cells”), which each include the primary transformed or transfected cell and progeny derived therefrom. Such progeny may not be completely identical in nucleic acid content to a parent cell and may contain mutations. Host cells notably include mammalian cells and bacterial cells. In some embodiments, the host cell is an immune cell.As used herein, the term “subject” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In preferred embodiments, the subject is a human.In some embodiments the subject has a disease or condition that can be treated with a polypeptide, nucleic acid encoding thereof, an ABP, a cell expressing thereof, or a pharmaceutical composition as provided herein. In some embodiments, the subject is suffering from or is at risk of a tumor or cancer. The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder” and “tumor” are generally used herein as synonyms. The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In some embodiments, the cell proliferative disorder is a cancer or a tumor.Cancers are classified by the type of cell that the tumor resembles and, therefore, the tissue presumed to be the origin of the tumor. The cancer may be a solid cancer or tumor or a “liquid tumor”.Liquid tumor are cancers affecting the blood, bone marrow and lymphoid system, also known as tumors of the hematopoietic and lymphoid tissues, which notably include leukemia and lymphoma. Liquid tumors include for example acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL), (including various lymphomas such as mantle cell lymphoma, non-Hodgkins’s lymphoma (NHL). Solid cancers as referred to herein typically include carcinomas, sarcomas, mesotheliomas, gliomas, germinomas, choriocarcinomas, blastoma or melanoma. Carcinomas are malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung, and colon cancer. Sarcomas are malignant tumors derived from connective tissue or mesenchymal cells. Mesotheliomas are tumors derived from the mesothelial cells lining the peritoneum and the pleura. Gliomas are tumors derived from glia, the most common type of brain cell. Germinomas are tumors derived from germ cells, normally found in the testicle and ovary. Choriocarcinomas are malignant tumors derived from the placenta.Cancers or tumors notably include cancer or tumor affecting any one of the following tissues or organs: breast; liver; kidney; heart, mediastinum, pleura; floor of mouth; lip; salivary glands; tongue; gums; oral cavity; palate; tonsil; larynx; trachea; bronchus, lung; pharynx, hypopharynx, oropharynx, nasopharynx; esophagus; digestive organs such as stomach, intrahepatic bile ducts, biliary tract, pancreas, small intestine, colon; rectum; urinary organs such as bladder, gallbladder, ureter; rectosigmoid junction; anus, anal canal; skin; bone; joints, articular cartilage of limbs; eyeand adnexa; brain; peripheral nerves, autonomic nervous system; spinal cord, cranial nerves, meninges; and various parts of the central nervous system; connective, subcutaneous and other soft tissues; retroperitoneum, peritoneum; adrenal gland; thyroid gland; endocrine glands and related structures; female genital organs such as ovary, uterus, cervix uteri; corpus uteri, vagina, vulva; male genital organs such as penis, testis and prostate gland; hematopoietic and reticuloendothelial systems; blood; lymph nodes; thymus.The tumor or cancer may be a primary tumor or a metastatic tumor or cancer. It is noteworthy that the terms cancer and tumors are used equally in the present application.Cancers includes also the cancers which are refractory to treatment with others chemotherapeutics. The term “refractory, as used herein refers to a cancer (and / or metastases thereof), which shows no or only weak antiproliferative response (e.g., no, or only weak inhibition of tumor growth) after treatment with another chemotherapeutic agent. These are cancers that cannot be treated satisfactorily with others chemotherapeutics. Refractory cancers encompass not only (i) cancers where one or more chemotherapeutics have already failed during treatment of a patient, but also (ii) cancers that can be shown to be refractory by other means, e.g., biopsy and culture in the presence of chemotherapeutics.The term “treating” (and variations thereof such as “treat” or “treatment”) refers as used herein, is defined as the application or administration of cells as per the disclosure or of a composition comprising the cells to a patient in need thereof with the purpose to reverse, alleviate, inhibit the progress of, or prevent the disorder or condition to which such term applies, or reverse, alleviate, inhibit the progress of, or prevent one or more symptoms of the disorder or condition to which such term applies. As used herein, the terms “treatment” or “treat” refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and include suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment."Treating cancer" includes, without limitation, reducing the number of cancer cells or the size of a tumor in the patient, reducing progression of a cancer to a more aggressive form (i.e. maintaining the cancer in a form that is susceptible to a therapeutic agent), reducing proliferation of cancer cells or reducing the speed of tumor growth, killing of cancer cells, reducing metastasis of cancer cells or reducing the likelihood of recurrence of a cancer in a subject. Treating a subject as used hereinrefers to any type of treatment that imparts a benefit to a subject afflicted with cancer or at risk of developing cancer or facing a cancer recurrence. Treatment includes improvement in the condition of the subject (e.g., in one or more symptoms), delay in the progression of the disease, delay in the onset of symptoms, slowing the progression of symptoms and others.As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of therapeutic product as provided herein or a pharmaceutical composition comprising thereof, when administered to a subject (optionally in combination with another therapeutic), is effective to treat a disease or disorder.The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.The terms “modulate”, and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.A “sample”, or “biological sample” as herein mentioned includes a sample of tissue, plasma, blood, or any other fluid from a subj ect. In some embodiments a biological sample includes a tumor sample from a cancer patient. Collection of patient samples, notably tumor patient’s samples are notably assembled in public databases such as the Cancer Genome Atlas (TCGA), a landmark cancer genomics program, molecularly characterized over 20,000 primary cancers and matched normal samples spanning more than 33 cancer types. A reference sample is typically a normal sample which can be analyzed in the same manner as a patient sample to provide reference value. A reference sample can be from the same or a different patient. A reference sample is typically from the sample tissue of the patient sample of interest. When the patient sample is a tumor sample, a reference sample can also be a juxta-tumor tissue sample.Tumor peptide antigen and peptide-MHC molecular complexPolypeptides and transcripts encoding thereof.Table 1Table 1 above provides the genomic references and coordinates of gene(s), transposable element(s) (also named herein repeated elements), splice junction (s) (i.e. breakpoint coordinates) andpeptide-encoding region(s) referred to in the present application. Further details on sequences, structures, genomic annotations and ID numbers (including SEQ ID references) of the transcripts and polypeptides of the present disclosure are disclosed in tables 6-9 of the present application.The inventors have shown that transcripts derived from the gene NIHCOLE, coding for a long noncoding RNA (see genomic coordinates in table 1 and below), are overexpressed in multiple tumor tissues while being expressed at low or undetectable levels in normal healthy cells and tissues. While the gene NIHCOLE is currently annotated as untranslated, the inventors have now provided evidence for the first time that polypeptides encoded by these transcripts can be translated, exposed at the surface of tumor cell, and targeted to produce an immune response.The present disclosure therefore encompasses a polypeptide comprising one or more target amino acid sequence(s) of at least 8 amino acids, wherein the target amino acid sequence:is encoded by a nucleic acid molecule derived from the gene NIHCOLE as referenced in Table 1;is encoded by a nucleic acid comprising a sequence of any one of SEQ ID NO: 1-55, a fragment or a variant thereof;is of any one of SEQ ID NO:56-11032, a fragment or a variant thereof; oris of any one of SEQ ID NO: 1033-1140 (see Table 9), or a variant thereof, notably a peptide of Table 10, notably apeptide of any one of SEQ ID NOs: SEQ ID NOs:1034, 1064, 1089, 1101 and 1131.In some embodiments, the polypeptide comprises one or more target amino acid sequence(s) having between 8 to 250 amino acids, notably between 8 and 200, between 8 and 150, between 8 and 50 amino acids. In some embodiments the target amino acid sequence is an MHC associated peptide (MAP) having 8 to 20 amino acids residues, notably 8 to 15, notably 8 to 12 amino acids, notably 9 to 15, 10 to 15 or 10 to 12 amino acid residues. As defined herein an MAP binds at least one MHC molecule with a KD binding affinity of 10'6M or less, or with an IC50 of less than 500 nM.In some embodiments, the one or more amino acid target sequence does not derive from, or does not consist essentially in a sequence that derives from, a genomic region of the gene NIHCOLE that is not unique and / or that is also annotated as (i.e. that overlaps) a transposable or repeated element (e.g. LTRs, LINEs, SINEs, or DNA transposons) whether the transposable or repeated element is annotated on the same or the opposite strand of NIHCOLE.By “unique sequence” it is intended herein that the target amino acid sequence has no more than 1 contiguous genomic sequence (i.e. corresponding to a single position in the genome), notably no contiguous genomic origin.In some embodiments, the one or more amino acid target sequence does not derive from or does not consist essentially in a sequence that derives from, a genomic region of the gene NIHCOLE that also overlaps the LINE repeat element L1PA2 located at chr5: 103,410,064- 103,416,082 (GRCh37).In some embodiments, the one or more amino acid target sequence does not derive from or does not consist essentially in a sequence that derives from, the genomic region located at chr5: 103,415,548-103,415,825 (GRCh37). This region typically corresponds to the genomic region that is overlapped by the exon 1 of NIHCOLE transcripts NIHCOLE-201: ENST00000514769.1, NIHCOLE-202: ENST00000662211.1, NIHCOLE-203: ENST00000665271.1, NIHCOLE-204: ENST00000666145.1, 2 NIHCOLE-05: ENST00000666455.2, NIHCOLE-206: ENST00000721479.1, NIHCOLE-207: ENST00000721481.1, NIHCOLE-208: ENST00000721482.1, NHICOLE-209: ENST00000721483.1, and NIHCOLE-211: ENST00000721485.1In some embodiments, the one or more amino acid target sequence does not derive from or does not consist essentially in a sequence that derive from, a genomic region of the gene NIHCOLE that also overlaps the LTR repeat element LTR12 located at chr5: 103,439,915-103,440,789 (GRCh37). It is however noteworthy that the present disclosure includes embodiments wherein the target amino acid sequence derives from a splice transcript variant. In such embodiments, the target sequence (notably the MAP sequence) can therefore comprise as a donor or acceptor sequence, a sequence that derives partially or totally from a TE sequence as above mentioned.In some embodiments the polypeptide comprises one or more target amino acid sequence(s) that is encoded by a transcript of the gene NIHCOLE as defined in table 1 above. In some embodiments, the polypeptide comprises one or more target amino acid sequence(s) that is / are encoded by a splice variant transcript of the gene NIHCOLE, said variant comprising the splice junction chr5: 103,416,742-103,417,581 (forward strand), also named herein “P12 junction” or “MIHI junction”.In some embodiments, the polypeptide comprises one or more MAP sequence(s) that derive(s) from a splice junction of a NIHCOLE splice transcript or variant thereof, notably between 2 annotated exons of NIHCOLE. As exemplified herein, a splice junction typically includes the MIHI junction as above mentioned (see also Table 1). The peptide of SEQ ID NO:252 is notably a MAP derived from the MIHI junction.In some embodiments, the transcripts of the gene NIHCOLE are annotated (according to GRCh38 or GRChl9 genome assembly). Currently, 12 transcripts have been annotated for the gene NIHCOLE (in hg!9 or in hg38 but see also Tables 2 and 5 for reference and genomic locations). In some embodiments, the polypeptide comprises one or more target amino acid sequences that is / are encoded by a splice variant transcript of the gene NIHCOLE selected from NIHC OLE-201: ENST00000514769.1, NIHCOLE-202: ENST00000662211.1, NIHCOLE-203: ENST00000665271.1, NIHCOLE-204: ENST00000666145.1, 2 NIHCOLE-05: ENST00000666455.2, NIHCOLE-206: ENST00000721479.1, and NIHCOLE-211: ENST00000721485.1.In some embodiments, the NIHCOLE transcript is not annotated.Non-annotated transcripts derived from the gene NIHCOLE according to the present disclosure, can be identified using computational tools allowing transcripts reconstruction, such as (but not limited to) StringTie (see for reference: PerteaM, Pertea GM, Antonescu CM, Chang TC, Mendell JT & Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads Nature Biotechnology 2015,) from RNAseq libraries obtained from cell lines and / or tissues sample collections (typically including, but not limited to, public libraries such as the GTEx RNAseq library, the TCGA RNAseq library and the CCLE RNAseq library).Annotated and non-annotated (i.e. StingTie reconstructed) transcripts of NIHCOLE are mentioned in SEQ ID NO: 1-55 of the Table 2 (genomic location of each transcript, including exon numbering and position per transcript are further provided in table 5). In some embodiments, the one or more target amino acid sequence is encoded by a nucleic acid sequence comprising a sequence of any one of SEQ ID NO: 1-55, a fragment or a variant thereof more particularly a sequence coding for a unique peptide according to Table 10. More particularly, the one or more target amino acid sequenceis encoded by a reading frame of a transcript of any one of SEQ ID NO: 1-55, a fragment or a variant thereof. Typically, only the strand coding for NIHCOLE is taken into consideration such that only the 3 reading frames of NIHCOLE are followed.In some embodiments, the one or more target amino acid sequence comprises a sequence as defined in any one of SEQ ID NO: 56- 1032, a fragment or a variant thereof, notably a sequence comprising a sequence of a unique peptide as defined in Table 10, more particularly a sequence of any one of SEQ ID NO: 72332, 405, 555, or 948.In some embodiments, the one or more target amino acid sequence is a MAP as defined above. In some embodiments, the MAP is selected among SEQ ID NO: 1033 to 1140 (see Table 9) and variants thereof, more particularly among the unique peptides of Table 10, more preferably among the sequence of any one of ID NOs:1034, 1064, 1089, 1101 and 1131.In some embodiments, the selected peptide as per the present invention and referred to above, is found only in tumor sample(s) and / or that is not found in healthy sample(s) (i.e. is expressed at a level and / or is detected at a level that is not significantly different from background or from a signal obtained in negative control conditions).In some embodiments, the peptides selected of Table 9 or 10, as referred to above, comprise peptides that are encoded by less than 5, notably less than 4, less than 3 contiguous genomic regions, 2 contiguous genomic regions, only a single contiguous genomic region, or by no contiguous genomic region (this is typically the case of polypeptides and MAPs derived from a junction sequence (e.g. a spliced sequence) wherein the donor and acceptor sequence of the junctions have 2 non-contiguous, distinct genomic origins). In particular, the MAP is of SEQ ID NO: 1034.In some embodiments, the peptides selected of Table 9 or 10, as referred to above, comprise peptides that are encoded by less than 50 transcripts, notably less than 40, less than 30, less than 20, less than 10, less than 5, less than 4, less than 3, less than 2, or by a single transcript, typically wherein the transcript is not expressed (or not significantly expressed) in healthy tissues.The transcripts are typically transcripts that expressed only in tumor cell or tissues, more preferably transcripts that are expressed at a level that is at least 2, at least 5, at least 10, at least 15, at least 20, at least 30, at least 50 or at least 100 higher in a tumor cell and / or in a tumor tissue as compared to the corresponding healthy cell or tissue.In some embodiments, the one or more target amino acid sequence comprises a sequence as defined in Table 9, Table 10 as well as variants thereof, more particularly among SEQ ID NOs:1034, 1064, 1089, 1101, 1131 and variants thereof.In some embodiments, the polypeptide may comprise more than one target amino acid sequences of at least 8 amino acids, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 29 or more targets amino acids sequences. The target sequences as previously defined can be selected from the same reading frame or not. The target sequences can also be selected from the same open reading frame or not. The two or more-target sequences of a polypeptide can be contiguous or not. Variants of the polypeptides and transcripts encoding thereofThe present disclosure further encompasses polypeptides and nucleic acids or transcripts encoding thereof that are variants of the peptides, nucleic acids (e.g. transcripts) as previously defined. It is understood and herein contemplated that the sequence of the target polypeptides, as well as polynucleotides encoding thereof, being disclosed it is well within the skill set of the skilled artisan to make variants of the amino acid and nucleic acid sequences thereof.It is also understood that one way to define any known variants and derivatives or those that might arise, of the disclosed polynucleotides and polypeptides herein is through defining the variants and derivatives in terms of homology and / or identify to specific known sequences. Specifically disclosed are variants of the polypeptides as disclosed herein and polynucleotides encoding thereof, which have at least, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 percent homology to the stated sequence. Those of skill in the art readily understand how to determine the homology of two polypeptide or polynucleotide sequences. Details about determination of homology are provided in the section related to definitions. For example, homology can be calculated after aligning the two sequences so that homology is at its highest level. Another way of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman and Wunsch, J. MoL Biol. 48: 443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85: 2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by inspection. The same type of homology can be obtained for nucleic acids by for example the algorithms disclosed in Zuker, M. Science 244:48-52, 1989, Jaeger et al. Proc. Natl. Acad. Sci. USA 86:7706-7710, 1989, Jaeger et al. Methods Enzymol. 183:281-306, 1989 which are herein incorporated by reference for at least material related to nucleic acid alignments.The present disclosure also encompasses, transcripts comprising a sequence coding for a variant of the polypeptide sequences as herein described, notably for a variant having at least 80 %, notably at least 90 %, at least 91 %, at least 92 %, at least 93 %, at least 94 %, at least at least 95 %, at least96 %, at least 97 %, at least 99 %, identity with the polypeptide sequences as herein described, notably the MAP sequences as herein described (see Table 9 notably Table 10 more particularly with any one of SEQ ID NOs: 1034, 1064, 1089, 1101, 1131).In some embodiments, a transcript of the present disclosure comprises a sequence selected from a variant of any one of SEQ ID NO: 1-55 or a fragment thereof and having at least 50 %, 60 %, 70 %, 80 %, 85 %, 90 %, 95 %, 98 %, 99 % identify with the said sequence or fragment.In embodiments, wherein the transcript comprises a variant of any one of SEQ ID NO: 1-55, the encoded amino acid sequence comprises a sequence having at least 80 % notably at least 90 %, at least 91 %, at least 92 %, at least 93 %, at least 94 %, at least at least 95 %, at least 96 %, at least 97 %, at least 99 %, identity with the polypeptide sequences as above mentioned.In some embodiments, a variant of MAPs as herein disclosed (i.e. SEQ ID NO: 199-285), notably a MAP of Table 9, notably of Table 10 more particularly of any one of SEQ ID NOs:1034, 1064, 1089, 1101, 1131 comprises at least 8, at least 9 or at least 10 contiguous amino acids of the said MAP sequence.In some embodiments, the polypeptide comprises a sequence having at least 50 %, 60 %, 65 %, 70 %, 75 %, 80 %, notably at least 90 %, at least 91 %, at least 92 %, at least 93 %, at least 94 %, at least at least 95 %, at least 96 %, at least 97 %, at least 99 %, identity with any one of SEQ ID NO:56-1032, notably with any one of the sequences of Table 9 or 10, or a fragment thereof.In some embodiments, the polypeptide comprises a sequence having at least 80 % notably at least 90 %, at least 91 %, at least 92 %, at least 93 %, at least 94 %, at least at least 95 %, at least 96 %, at least 97 %, at least 99 % identity with any one of the MAPs described in Table 9 or 10, more particularly with any one of SEQ ID NOs:1034, 1064, 1089, 1101 and 1131. In some embodiments, the variant comprises at least 8, at least 9 or at least 10 contiguous amino acids of the said MAP sequence. In some embodiments, the polypeptide comprises a target amino acid sequence having at least 6, at least 7, at least 8, at least 9 or at least 10 contiguous amino acids of any one of the peptide sequences of Table 9 or 10, more particularly with any one of SEQ ID NOs: 1034, 1064, 1089, 1101 and 1131.The present disclosure also encompasses isoleucine and / or leucine variants of any one of the polypeptides as described herein (Table 8-10, notably any one of SEQ ID NO: 72 332, 405, 555, 948 or any one of SEQ ID NOs: 1034, 1064, 1089, 1101 and 1131). For example, the present disclosure encompasses:a variant of the MIHIHSHPK (SEQ ID NO: 1034) peptide wherein one or two of the isoleucine (I) residues in positions 2 and 4 of the peptide is replaced by a leucine (L) residue,a variant of the YLSLILNRI peptide (SEQ ID NO: 1089) wherein one or more of the leucine (L) residues in any one of the positions 2, 4 and 6 is replaced by an isoleucine residue (I) and / or one or two of the isoleucine residues in any one of positions 5 and 9 is replaced by a leucine residue, a variant of the RLKRVIILL peptide (SEQ ID NO: 1131) wherein one or more of the leucine (L) residues in any one of the positions 2, 6 and 9 is replaced by and isoleucine residue (I) and / or one or two of the isoleucine residues in any one of positions 6 and 7 is replaced by a leucine residue. Typically, the variant has the same or a decreased KD binding affinity for the one or more MHC molecule that is bound by the parent sequence.A peptide of the present disclosure can be subject to various variations or changes, such as substitutions (either conservative or non-conservative), addition, or deletion in amino acid residues, as well as alteration in the order or composition of certain residues, where such changes might provide for certain advantages in their use (such as improved MHC binding, stability or presentation, or improved immunogenicity). For example, modifications of the peptide sequence with various amino acid mimetics or unnatural amino acids can be particularly useful in increasing its stability in vivo or its immunogenicity.Assays for assessment of MHC binding and immunogenicity according to the present disclosure are described and exemplified in the following section.Stability can be assayed in a number of ways. For instance, peptidases and various biological media, such as human plasma and serum, have been used to test stability (see, e.g., Verhoef et ah, Eur. J. Drug Metab Pharmacokin. 11:291-302 (1986)). Half- life of the peptides can be conveniently determined using a 25% human serum (v / v) assay. The protocol is generally as follows. Pooled human serum (Type AB, non-heat inactivated) is delipidated by centrifugation before use. The serum is then diluted to 25% with RPMI tissue culture media and used to test peptide stability. At predetermined time intervals a small amount of reaction solution is removed and added to either 6% aqueous trichloracetic acid or ethanol. The cloudy reaction sample is cooled (4 degrees C) for 15 minutes and then spun to pellet the precipitated serum proteins. The presence of the peptides is then determined by reversed-phase HPLC using stability-specific chromatography conditions. It is readily appreciated that certain amino acid residues essential for biological activity, e.g., those at critical contact sites or conserved residues, may generally not be altered without an adverse effect on biological activity.Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final peptide or polypeptide.Peptide sequences as herein disclosed can be modified by the substitution of one or more residues at different, possibly selective, sites within the peptide chain, if not otherwise stated. A variant of apolypeptide of the disclosure may thus contain a number of substitutions, for example, conservative substitutions (for example, 1-25, such as 1-10, in particular any of 1, 2, 3, 4 or -5, and especially 1 amino acid residue(s) may be altered) when compared to the reference sequence. The number of substitutions, for example, conservative substitutions, may be up to 20% e.g., up to 10% e.g., up to 5% e.g., up to 1% of the number of residues of the reference sequence.An amino acid substitution typically includes a conservative substitution. By “conservative substitution” it is meant replacing an amino acid residue with another which is biologically and / or chemically similar, e.g., one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as Gly, Ala; Vai, he, Leu, Met; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr. The effect of single amino acid substitutions may also be probed using D-amino acids. Such modifications can be made using well known peptide synthesis procedures, as described in e.g., Merrifield, Science 232:341- 347 (1986), Barany & Merrifield, The Peptides, Gross & Meienhofer, eds. (N.Y., Academic Press), pp. 1-284 (1979); and Stewart & Young, Solid Phase Peptide Synthesis, (Rockford, Ill., Pierce), 2d Ed. (1984). The non-critical amino acids need not be limited to those naturally occurring in proteins, such as L-a-amino acids, or their D-isomers, but may include non-natural amino acids as well, such as P-y-8-amino acids, as well as many derivatives of L-a-amino acids.Conservative substitution tables providing functionally similar amino acids are well known in the art. Variants can include homologues of polypeptides found in other species.Conservative substitutions can be defined as exchanges within one of the following five groups: Group 1 - small aliphatic, nonpolar or slightly polar residues (Ala, Ser, Thr, Pro, Gly); Group 2 -polar, negatively charged residues and their amides (Asp, Asn, Glu, Gin); Group 3 - polar, positively charged residues (His, Arg, Lys); Group 4 - large, aliphatic, nonpolar residues (Met, Leu, he, Vai, Cys); and Group 5 - large, aromatic residues (Phe, Tyr, Trp). Conservative substitutions may include those, which are described by Dayhoff in “The Atlas of Protein Sequence and Structure. Vol. 5”, Natl. Biomedical Research, the contents of which are incorporated by reference in their entirety. Lor example, in an aspect, amino acids, which belong to one of the following groups, can be exchanged for one another, thus, constituting a conservative exchange: Group 1 : alanine (A), proline (P), glycine (G), asparagine (N), serine (S), threonine (T); Group 2: cysteine (C), serine (S), tyrosine (Y), threonine (T); Group 3: valine (V), isoleucine (I), leucine (L), methionine (M), alanine (A), phenylalanine (L); Group 4: lysine (K), arginine (R), histidine (H); Group 5: phenylalanine (L), tyrosine (Y), tryptophan (W), histidine (H); and Group 6: aspartic acid (D), glutamic acid (E). In an aspect, a conservative amino acid substitution may be selected from the following of T — >A, G — >A, A — >1, T — >V, AAM, T — >1, AAV, TAG, and / or T — >S. A conservative amino acid substitution may include the substitution of an amino acid by another amino acid of the same class,for example, (1) nonpolar: Ala, Vai, Leu, lie, Pro, Met, Phe, Trp; (2) uncharged polar: Gly, Ser, Thr, Cys, Tyr, Asn, Gin; (3) acidic: Asp, Glu; and (4) basic: Lys, Arg, His. Other conservative amino acid substitutions may also be made as follows: (1 ) aromatic: Phe, Tyr, His; (2) proton donor: Asn, Gin, Lys, Arg, His, Trp; and (3) proton acceptor: Glu, Asp, Thr, Ser, Tyr, Asn, Gin (see, for example, U.S. Patent No. 10,106,805, the contents of which are incorporated by reference in their entirety).The following eight groups each also contain amino acids that are typically conservative substitutions for one another:1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E);3) Asparagine (N), Glutamine (Q);4) Arginine (R), Lysine (K);5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);7) Serine (S), Threonine (T); and8) Cysteine (C), Methionine (M)(see, e.g., Creighton, Proteins 1984).Amino acid substitutions can also be made in accordance with Table 3 below, when it is desired to finely modulate the characteristics of the peptide.Table 3: Well described amino acid residue substitutions.Typically, a series of peptides with single amino acid substitutions are employed to determine the effect of electrostatic charge, hydrophobicity, etc. on binding. For instance, a series of positively charged (e.g., Lys or Arg) or negatively charged (e.g., Glu) amino acid substitutions are made along the length of the peptide revealing different patterns of sensitivity towards various MHC molecules and T cell receptors. In addition, multiple substitutions using small, relatively neutral moieties such as Ala, Gly, Pro, or similar residues may be employed. The substitutions may be homo-oligomers or hetero-oligomers. The number and types of residues which are substituted or added depend on the spacing necessary between essential contact points and certain functional attributes which are sought (e.g., hydrophobicity versus hydrophilicity). Increased binding affinity for an MHC molecule or T cell receptor may also be achieved by such substitutions, compared to the affinity of the parent peptide. In any event, such substitutions should employ amino acid residues or other molecular fragments chosen to avoid, for example, steric and charge interference which might disrupt binding.Substantial changes in function (e.g., affinity for MHC molecules or T cell receptors) can also be made by selecting substitutions that can be less conservative than those in above table, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in peptide properties will be those in which (a) hydrophilic residue, e.g. seryl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a residue having an electropositive side chain, e.g., lysl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g. glutamyl or aspartyl; or (c) a residue having a bulky side chain, e.g. phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine.The peptides and polypeptides variants may also comprise isosteres of two or more residues in the parent peptide or polypeptides. An isostere as defined here is a sequence of two or more residues that can be substituted for a second sequence because the steric conformation of the first sequence fits a binding site specific for the second sequence. The term specifically includes peptide backbone modifications well known to those skilled in the art. Such modifications include modifications of the amide nitrogen, the a-carbon, amide carbonyl, complete replacement of the amide bond, extensions, deletions or backbone crosslinks. See, generally, Spatola, Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, Vol. VII (Weinstein ed., 1983)."Variants" of peptide sequences as herein disclosed also include peptides wherein the side chains of, for example, one or two of the amino acid residues are altered (for example by replacing them with the side chain of another naturally occurring amino acid residue or some other side chain) such that the peptide is still able to bind to an HLA molecule in substantially the same way as non-variant peptide sequence (typically the MIHI peptide as herein disclosed).Preferably those substitutions are located at the end of the amino acid chain. Such substitutions may be of a conservative nature, for example, where one amino acid is replaced by an amino acid of similar structure and characteristics, such as where a hydrophobic amino acid is replaced by another hydrophobic amino acid. Even more conservative would be replacement of amino acids of the same or similar size and chemical nature, such as where leucine is replaced by isoleucine. In studies of sequence variations in families of naturally occurring homologous proteins, certain amino acid substitutions are more often tolerated than others, and these often show similarities in size, charge, polarity, and hydrophobicity between the original amino acid and its replacement, and such is the basis for defining “conservative substitutions”.Substitutions may also involve structures other than the common L-amino acids. Thus, D-amino acids might be substituted for the L-amino acids commonly found in the antigenic peptides of the disclosure and yet still be encompassed by the disclosure herein. In addition, non-standard amino acids (i.e., other than the common naturally occurring proteinogenic amino acids) may also be used for substitution purposes to produce immunogens and immunogenic polypeptides according to the present disclosure. If substitutions at more than one position are found to result in a peptide with substantially equivalent or greater antigenic activity as defined below, then combinations of those substitutions will be tested to determine if the combined substitutions result in additive or synergistic effects on the antigenicity of the peptide.A peptide consisting essentially of the amino acid sequence as indicated herein can have one or two non-anchor amino acids (see below regarding the anchor motif) exchanged without its ability to bind to an MHC molecule class I or II being substantially changed or negatively affected, when compared to the non-modified peptide. In another embodiment, in a peptide consisting essentially of the amino acid sequence as indicated herein, one or two amino acids can be exchanged with their conservative exchange partners (see herein below) without the ability to bind to an MHC molecule class I or II being substantially changed, or is negatively affected, when compared to the nonmodified peptide.The amino acid residues that do not substantially contribute to interactions with the T cell receptor can be modified by replacement with other amino acids whose incorporation does not substantially affect T cell reactivity and does not eliminate binding to the relevant MHC. Thus, apart from the proviso given, the peptide of the disclosure may be any peptide (by which term the inventors includeoligopeptide or polypeptide), which includes the amino acid sequences, or a portion or variant thereof as given.Substitutional or deletional mutagenesis can be employed to insert sites for N-glycosylation (Asn-X-Thr / Ser) or O-glycosylation (Ser or Thr). Deletions of cysteine or other labile residues also may be desirable. Deletions or substitutions of potential proteolysis sites, e.g. Arg, is accomplished for example by deleting one of the basic residues or substituting one by glutaminyl or histidyl residues. Certain post-translational derivatizations are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and asparyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the o-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco pp 79-86

[1983] ), acetylation of the N-terminal amine and, in some instances, amidation of the C-terminal carboxyl.It is understood that the description of conservative mutations and homology can be combined together in any combination, such as embodiments that have at least 70% homology to a particular sequence wherein the variants are conservative mutations.Longer (elongated) peptides may also be suitable. It is possible that MHC class I epitopes, although usually between 8 and 12 amino acids long, are generated by peptide processing from longer peptides or proteins that include the actual epitope. It is preferred that the residues that flank the actual epitope are residues that do not substantially affect proteolytic cleavage necessary to expose the actual epitope during processing.The sequences as herein disclosed (including the MAP sequences of table 4, such as the MUH peptide) can be elongated by up to four amino acids, which is 1, 2, 3 or 4 amino acids can be added to either end in any combination between 4:0 and 0:4.Polypeptide variants also include those wherein additional amino acids are inserted compared to the reference sequence, for example, such insertions may occur at 1-10 locations (such as any of 1, 2, 3, 4 or 5 locations, suitably 1 or 2 locations, in particular 1 location) and may, for example, involve the addition of 50 or fewer amino acids at each location (such as 20 or fewer, in particular 10 or fewer, especially 5 or fewer). Suitably such insertions do not occur in the region of an epitope, and do not therefore have a significant impact on the immunogenic properties of the polypeptide. One example of insertions includes a short stretch of histidine residues (e.g., 2-6 residues) to aid expression and / or purification of the antigen in question.Polypeptide variants include those wherein amino acids have been deleted compared to the reference sequence, for example, such deletions may occur at 1-10 locations (such as any of 1, 2, 3, 4 or 5 locations, suitably 1 or 2 locations, in particular 1 location) and may, for example, involve the deletion of 50 or fewer amino acids at each location (such as 20 or fewer, in particular 10 or fewer, especially 5 or fewer). Suitably such deletions do not occur in the region of an epitope, and do not therefore have a significant impact on the immunogenic properties of the polypeptide. It is understood that there are numerous amino acid and peptide analogs which can be incorporated into the disclosed compositions. The opposite stereo isomers of naturally occurring peptides are disclosed, as well as the stereo isomers of peptide analogs. These amino acids can readily be incorporated into polypeptide chains by charging tRNA molecules with the amino acid of choice and engineering genetic constructs that utilize, for example, amber codons, to insert the analog amino acid into a peptide chain in a site specific way.Molecules can also be produced that resemble peptides, but which are not connected via a natural peptide linkage. For example, linkages for amino acids or amino acid analogs can include CH2NH— , — CH2S— , — CH2— CH2— , — CH=CH— (cis and trans), — COCH2— , — CH(OH)CH2 — , and — CHH2SO — (These and others can be found in Spatola, A. F. in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Vega Data (March 1983), Vol. 1, Issue 3, Peptide Backbone Modifications (general review); Morley, Trends Pharm Sci (1980) pp. 463-468; Hudson, D. et al., Int J Pept Prot Res 14: 177-185 (1979) (— CH2NH— , CH2CH2— ); Spatola et al. Life Sci 38: 1243-1249 (1986) (—CH H2— S); Hann J. Chem. Soc Perkin Trans. I 307-314 (1982) (— CH— CH— , cis and trans); Almquist et al. J. Med. Chem. 23:1392-1398 (1980) ( — COCH2 — ); Jennings-White et al. Tetrahedron Lett 23:2533 (1982) ( — COCH2 — ); Szelke et al. European Appln, EP 45665 CA (1982): 97:39405 (1982) (— CH(OH)CH2— ); Holladay et al. Tetrahedron. Lett 24:4401-4404 (1983) (— C(OH)CH2— ); andHruby Life Sci 31:189-199 (1982) (— CH2— S— ); each of which is incorporated herein by reference. A particularly preferred non-peptide linkage is — CH2NH — . It is understood that peptide analogs can have more than one atom between the bond atoms, such as b-alanine, g-aminobutyric acid, and the like.Amino acid analogs and analogs and peptide analogs often have enhanced or desirable properties, such as, more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., abroad-spectrum of biological activities), reduced antigenicity, and others. The peptides of the present disclosure can be notably modified to provide desired attributes other than improved serum half-life. For instance, the ability of the peptide to induce CTL activity can be enhanced by linkage to a sequence which contains at least one epitope that is capable of inducing a T helper cell response. Immunogenicpeptides / T helper conjugates can be linked by a spacer molecule. The spacer is typically comprised of relatively small, neutral molecules, such as amino acids or amino acid mimetics, which are substantially uncharged under physiological conditions. The spacers are typically selected from, e.g., Ala, Gly, or other neutral spacers of nonpolar amino acids or neutral polar amino acids. It will be understood that the optionally present spacer need not be comprised of the same residues and thus can be a hetero- or homo-oligomer. When present, the spacer will usually be at least one or two residues, more usually three to six residues. Alternatively, the peptide can be linked to the T helper peptide without a spacer.The peptides or polypeptides sequences can be linked to the T helper peptide either directly or via a spacer either at the amino or carboxy terminus of the peptide. The amino terminus of peptides of the present disclosure can be acetylated. Exemplary T helper peptides include tetanus toxoid 830-843, influenza 307-319, malaria circumsporozoite 382-398 and 378-389.In some embodiments, the present disclosure also encompasses a synthetic or recombinant labelled (notably synthetic heavy-labelled) variant of a target peptide (i.e. target MAP) herein described, notably a peptide of Table 9, 10 or a peptide of any one of SEQ ID Nos: 1034, 1064, 1089, 1101 and 1131 or a variant thereof as above defined. Such labelled peptide (notably heavy labelled peptide) is typically usable in MS-based (typically targeted Liquid Chromatography-Tandem Mass Spectrometry - LC MS / MS) detection of a target peptide (i.e. MAP) of the present disclosure in a biological tissue or cell sample of or in a cell line as notably illustrated in the Examples herein. As this specification discusses various proteins and protein sequences it is understood that the nucleic acids that can encode those protein sequences are also disclosed. This would include all degenerate sequences related to a specific protein sequence, i.e. all nucleic acids having a sequence that encodes one particular protein sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed protein sequence. MHC binding and immunogenicityThe present disclosure encompasses polypeptides as previously defined, as well as transcripts encoding thereof, that comprise at least one MHC type I epitope, wherein this MHC type I epitope binds one or more MHC type I molecule, typically from the same class or the same supertype. MHC type I epitopes typically comprise between 8 to 12 amino acid residues.In some embodiments, the polypeptide is encoded by an open reading frame (ORF) of a transcript that codes for one or more MHC type I epitopes. When the polypeptide comprises more than one MHC type I epitopes, the two or more epitopes can bind the same or different MHC type I molecule,the same or different MHC type I supertype and / or the same or different MHC type I class. In some embodiments, the polypeptide comprises a sequence of any one of SEQ ID NO: 56- 1032 a variant, or a fragment thereof. In some embodiments the polypeptide is encoded by an ORF of any one of the transcripts of SEQ ID NO: 1-55, notably an ORF of a transcript coding for the MIHI peptide (e.g. of SEQ ID NO: 72 and 1034).In some embodiments, these polypeptides further comprise at least one MHC type II epitope. The present disclosure also encompasses MHC restricted peptides, or MAP, of 8-12 amino acid residues, as previously defined, that bind at least one MHC type I molecule with a binding affinity (Kd) of less than 10'6M (see notably below for details) and / or with an IC50 of less than 500 nM. In embodiments, wherein the MAP binds more than one MHC molecule, the two or more MHC molecules can be of the same class or the same supertype.The inventors have shown that the MIHI peptide of SEQ ID NO: 1034 specifically binds HLA-A molecules, notably molecules from the HLA A*03 supertypes, in particular HLA A*03 and HLA A*011 molecules, even more particularly HLA A* 03:01 and HLA A* 11:01, with a binding affinity (KD also named Kd herein) of less than 1 micro M, notably less 100 nM. Typically, a variant of the MIHI peptide as previously defined exhibits a binding affinity for an HLA A* 03 and / or an HLA A*011 molecule that is at least in the same range or that is increased (i.e. decreased Kd value) as compared to the MIHI peptide of SEQ ID NO: 1034. The present disclosure also encompasses variants of the MIHI peptide as previously defined that bind an HLA A*03 and / or HLA A*011 molecules with a binding affinity (Kd) of less than 100 nM, notably less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM or less than 1 nM (typically comprised between 1.1 O'10and 1.1 O'12M or as detailed below).The inventors have shown that the peptide of SEQ ID NO: 1064 specifically binds HLA-A molecules, notably molecules from the HLA A*03 supertypes, in particular HLA A*03 and HLA A*011 molecules, even more particularly HLA A*03:01 and HLA A*11:01, with a binding affinity (KD also named Kd herein) of less than 1 micro M, notably less 100 nM. Typically, a variant of the peptide of SEQ ID NO: 1064 as previously defined exhibits a binding affinity for an HLA A*03 and / or an HLA A*011 molecule that is at least in the same range or that is increased (i.e. decreased Kd value) as compared to the peptide of SEQ ID NO: 1064. The present disclosure also encompasses variants of the peptide of SEQ ID NO: 1064 as previously defined that bind an HLA A*03 and / or HLA A*011 molecules with a binding affinity (Kd) of less than 100 nM, notably less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM or less than 1 nM (typically comprised between 1.10"10and 1.1 O'12M or as detailed below).The inventors have also shown that the peptide of SEQ ID NO: 1089 specifically binds HLA-A molecules, notably molecules from the HLA A*02 supertypes, in particular HLA A*02:01 molecules with a binding affinity (KD) of less than 1 microM, notably less 100 nM. Typically, a variant of the peptide of SEQ ID NO: 1089, as previously defined, exhibits a binding affinity for an HLA A* 02 molecule, notably for an HLA A*02:01 that is at least in the same range or that is increased (i.e. decreased KD value) as compared to the peptide of SEQ ID NO: 1089. The present disclosure also encompasses variants of the peptide of SEQ ID NO: 1089 as previously defined that binds an HLA A* 02 molecules, notably an HLA A*02:01 molecule with a binding affinity (KD) of less than 100 nM, notably less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM or less than 1 nM (typically comprised between 1.1 O'10and 1.1 O'12M or as detailed below).The inventors have also shown that the peptide of SEQ ID NO: 1101 specifically binds HLA-A molecules, notably molecules from the HLA A*02 supertypes, in particular HLA A*02:01 molecules with a binding affinity (KD) of less than 1 microM, notably less 100 nM. Typically, a variant of the peptide of SEQ ID NO: 1101, as previously defined, exhibits a binding affinity for an HLA A*02 molecule, notably for an HLA A*02:01 that is at least in the same range or that is increased (i.e. decreased KD value) as compared to the peptide of SEQ ID NO: 1101. The present disclosure also encompasses variants of the peptide of SEQ ID NO: 1101 as previously defined that binds an HLA A*02 molecules, notably an HLA A*02:01 molecule with a binding affinity (KD) of less than 100 nM, notably less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM or less than 1 nM (typically comprised between 1.1 O'10and 1.1 O'12M or as detailed below).The inventors have also shown that the peptide of SEQ ID NO: 1131 specifically binds HLA-A molecules, notably molecules from the HLA A*02 supertypes, in particular HLA A*02:01 molecules with a binding affinity (KD) of less than 1 microM, notably less 100 nM. Typically, a variant of the peptide of SEQ ID NO: 1131, as previously defined, exhibits a binding affinity for an HLA A*02 molecule, notably for an HLA A*02:01 that is at least in the same range or that is increased (i.e. decreased KD value) as compared to the peptide of SEQ ID NO: 1131. The present disclosure also encompasses variants of the peptide of SEQ ID NO: 1131 as previously defined that binds an HLA A*02 molecules, notably an HLA A*02:01 molecule with a binding affinity (KD) of less than 100 nM, notably less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM or less than 1 nM (typically comprised between 1.1 O'10and 1.1 O'12M or as detailed below).Typically, an MHC or an HLA type I epitope of the present disclosure binds an HLA-type I molecule with a binding affinity (Kd) of less than about 10'6M, notably less than 10'7M, less than 10'8M, or less than 10'9M. Typically the binding affinity of a pMHC for and Type I HLA is comprised between 0,1 nM and lOOOnM, notably between 0,1 and 100 nM, between 1 and 100 nM, between 0,1 and 10 nM, between 1 and 10 nM.Affinity can also be measured in terms of its half-maximal inhibitory concentration (ICso), such that typically a pMHC or an HLA type I epitope of the present disclosure binds an HLA-type I molecule with an IC50 of less than 5000 nM, notably less than 500 nM, notably less than 50 nM. Typically, the IC50 is comprised between 5 and 5000 nM, notably between 5 and 500 nM, between 5 and 50 nM, between 50 and 5000 nM or between 50 and 500 nM.Peptide-HLA binding affinities can be predicted using a predictive process, e.g. artificial neural networks such as NetMHCpan (see Jurtz V et al. NetMHCpan-4.0: Improved Peptide- -MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data. The Journal of Immunology 199, 3360- -3368 (2017); Nielsen M & Andreatta M NetMHCpan- 3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets. Genome Med. 8, 33 (2016) and Reynisson, Birkir et al. “NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. ” Nucleic acids research vol. 48, W1 (2020): W449-W454. doi: 10.1093 / nar / gkaa379), MixMHCPred (see Gfeller, David et al. “Improved predictions of antigen presentation and TCR recognition with MixMHCpred2.2 and PRIME2.0 reveal potent SARS-CoV-2 CD8+ T-cell epitopes.” Cell systems vol. 14,1 (2023): 72- 83. e5), MHCFlurry (() Donnell, Timothy J et al. “MHCflurry 2.0: Improved Pan-Allele Prediction of MHC Class I-Presented Peptides by Incorporating Antigen Processing. ” Cell systems vol. 11,1 (2020): 42-48. e7), or HEAthena (see Sarkizova, Siranush et al. “A large peptidome dataset improves HLA class I epitope prediction across most of the human population. ” Nature biotechnology vol. 38,2 (2020): 199-209). See also the recent review of Mei, S. et al. (Briefings Bioinform. 21, 1119-1135 (2020)) summarizing and comparing current in silico predictions tools “A comprehensive review and performance evaluation of bioinformatics tools for HLA class I peptide-binding prediction” .Experimental assays to evaluate the affinities of MHC -I epitopes have been developed over the last 30 years using both cell-based and cell-free platforms, preferably high-throughput assays. The main types of binding assays (including cell-based or cell free types) include competitive binding assays (using radiolabeled or fluorescently labeled competing peptide), direct binding assays (such as SPR analysis), stability-based assays and ELISA-based assays. Some of the mostly used assays are further detailed below with some example references. Experimental binding characteristics (e.g.: IC50 and Kd values) can be obtained notably using high-throughput in vitro binding assays as described herein in the “definition” section. Both in the silico prediction and the (preferably high-throughput (HTP)) binding assay(s) can be used in combination. The predicted binding affinities of a peptide antigen to the HLA protein of interest is preferably highly correlated with the resulting experimental binding affinities found through the binding assays.A well-used method for quantifying peptide affinity for HLA molecules involves cell-free biochemical methods to measure binding of iodinated peptides to MHC-I (see for example Sette A, Sidney J, del Guercio MF, Southwood S, Ruppert J, Dahlberg C, Grey HM, Kubo RT, “Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays”, Mol. Immunol 31 (1994) 813-822). Using this technique, MHC-I molecules are purified from cell lysates and solubilized in detergent, and affinity can be measured by quantifying binding of radiolabeled peptides by gel filtration of MHC-I complexes vs. free peptide. Other methods employed fluorescence labeling rather than iodination, thereby eliminating the radioactive waste and hazard, but still required purification of each peptide-MHC-I complex by chromatographic or electrophoretic separation. A high-throughput scintillation proximity assay based on radioactive peptide exchange using purified native MHC-I protein has also been (see Hamdahl M, Rasmussen M, Roder G, Buus S, “Real-time, high-throughput measurements of peptide-MHC-I dissociation using a scintillation proximity assay”, J. Immunol. Methods 374 (2011) 5 12).Cell-based assays can also be used to evaluate MHC-I-peptide interactions, including a cell-surface stabilization assay, in which surface MHC-I of TAP-deficient T2 cells is stabilized by the addition of iodinated or fluorescently-labeled peptides (see Schumacher TN, Heemels MT, Neefjes JJ, Kast WM, Melief CJ, Ploegh HL, Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro, Cell 62 (1990) 563-567; or Hosken NA, Bevan MJ, Defective presentation of endogenous antigen by a cell line expressing class I molecules, Science 248 (1990) 367-370) as well as cell-surface binding assays, in which endogenous peptides are exchanged in situ (see Kessler JH, Benckhuijsen WE, Mutis T, Melief CJ, van der Burg SH, Drijfhout JW, “Competition-based cellular peptide binding assay for HLA class I” (Chapter 18), Curr. Protoc. Im 61 (1) (2004) Unit 18 12; or Kessler JH, Mommaas B, Mutis T, Huijbers I, Vissers D, Benckhuijsen WE, Schreuder GM, Offringa R, Goulmy E, Melief CJ, van der Burg SH, Drijfhout JW, “Competition-based cellular peptide binding assays for 13 prevalent HLA class I alleles using fluorescein-labeled synthetic peptides ”, Hum. Immunol 64 (2003) 245-255) or partially removed by acid treatment of surface MHC-I-bound peptides followed by addition of fluorescent peptides (Torkus WJ, Zeh HJ 3rd, Salter RD, Lotze MT, Identification of T-cell epitopes: rapid isolation of class I-presented peptides from viable cells by mild acid elution, J. Immunother. Emphas. Tumor Immunol 14 (1993) 94-103).Surface plasmon resonance can also be used to measure peptide binding in indirect assays monitoring P2-microglobulin dissociation (Miles KM, Miles JJ, Madura F, Sewell AK, Cole DK, Real time detection of peptide-MHC dissociation reveals that improvement of primary MHC-binding residues can have a minimal, or no, effect on stability, Mol. Immunol 48 (2011) 728-732), and in direct assays following MHC-I binding to covalently-coupled peptides (Khilko SN, JelonekMT, Corr M, Boyd LF, Bothwell AL, Margulies DH, Measuring interactions of MHC class I molecules using surface plasmon resonance, J. Immunol. Methods 183 (1995) 77- -94).The peptide dependence of in vitro MHC -I folding reactions can also serve as the basis for MHC-I-peptide binding assays, with detection using conformation-specific antibodies or pairs of antibodies specific for MHC -I heavy-chain and P2-microglobulin.Another assay is based on a method wherein a weakly-binding peptide covalently attached to the N-terminus of the MHC -I 02m subunit is released from the peptide binding site after proteolytic cleavage of the linker. The resultant protein is then able to bind an added labeled peptide. Peptide binding can be followed using fluorescence polarization (a technique wherein plane-polarized light is employed to distinguish between bound and free ligands without the need for physical separation) in a direct binding assay. The labeled peptide will exhibit high fluorescence polarization when bound to MHC -I due to decreased molecular mobility but will tumble freely in solution and display low polarization when unbound. Titration of unlabeled competitor peptides allows for computation of binding affinities.A competition binding assay using the same principle can also be implemented using unlabeled test peptides and a single labeled probe peptide and can be used to give half-maximal inhibition (IC50) values that report relative binding affinity of test peptides and estimates of inhibitor peptide-binding constant (Ki) (Jurewicz, Mollie M et al. “MHC-I peptide binding activity assessed by exchange after cleavage of peptide covalently linked to [C-microglobulin. ” Analytical biochemistry vol. 584 (2019): 113328).In some embodiments, confirmation of the binding of an MHC I molecule to a MAP as per the present disclosure can also be performed by mass spectrometry, using monoallelic cell lines expressing HLA molecules (for example an HLA deficient - typically CRISPR / Cas9 engineered-antigen presenting cell line (e.g., HMy2.ClR) transduced with HLA I molecules of interest) that can be electroporated with minigenes containing one or several antigens. Then (engineered) monoallelic cell lines containing the antigen minigene(s) may be processed for targeted mass spectrometry assays (optionally following Class-I HLA enrichment).In some embodiments, a peptide exchange assay or other cell-based assays may be used to identify HLA type I binding peptides. For example, a plurality of HLA class I epitopes, obtained after cleavage by a single or a plurality of antigens, may be used for the peptide exchange assay. Other examples of assays further include, e.g., complex detection assays, HLA binding ligand identification assays, native SEC-MS and CE-MS methods, or others described in PCT Application No. PCT / EP2019 / 066811, the content of which is incorporated by reference herein to its entirety.Another assay uses engineer stabilizing disulfides in the HLA allele to enable the formation of stable MHC I complexes in the presence of a dipeptide. These disulfide-stabilized MHCI reagents have been referred to as “empty” MHCI complexes and can be loaded with a peptide or epitope by simply adding the peptide of interest to the empty MHCI complex (see Moritz A, Anjanappa R, Wagner C, et al. High-throughput peptide -MHC complex generation and kinetic screenings of TCRs with peptide -receptive HLA-A*02:01 molecules. Sci Immunol. 2019:4:eaav-860: and Saini SK, Tamhane T, Anjanappa R, et al. Empty peptide -receptive MHC class I molecules for efficient detection of antigen -specific T cells. Sci Immunol. 2019; 4: eaau9039). One other assay uses an allele-specific UV-cleavable peptide, also called a conditional MHCI ligand, to form an MHCI complex, in which the peptide binds with high affinity when intact and low affinity when cleaved (see Rodenko B, Toebes M, Hadrup SR, et al. Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat Protoc. 2006;! : 1120-1132). See also for more general reference Darwish, Martine et al. “High-throughput identification of conditional MHCI ligands and scaled-up production of conditional MHCI complexes. ” Protein science : a publication of the Protein Society vol. 30,6 (2021): 1169-1183.In some embodiments, immunogenicity assays (see below), notably MHC multimer assays, can be used to provide an indirect assessment of the MHC -peptide complex and therefore to identify MHC peptides binding to MHC type I molecules.Suitably a polypeptide of the present disclosure is immunogenic. Typically an MHC associated peptide as herein described can trigger an immune response (notably a T cell response) when presented in combination with an MHC molecule at the cell surface , in particular they are able to induce, when associated with said MHC molecule, a T cell cross-reacting with said peptide.Typical in vitro assays used to assess immunogenicity include T cell activation, T cell proliferation and T cell-directed tumor killing (cytotoxic) assays (e.g. CTL assay). Well-used methods for tracking T-cell responses include notably ELISPOT (Enzyme-Linked ImmunoSpot) and MHC multimer staining. The ELISPOT assay is a functional assay that measures cytokine (e.g. IFN-y, TNF-a, or IL-2) release from T cells upon stimulation of PBMCs (APC) loaded with the peptide antigen. This assay ideally provides a functional readout. MHC multimer assays (e.g., tetramer, pentamer, dextramer assays) are broadly used to detect and quantify antigen-specific T cells by using fluorescently labeled MHC -peptide complexes that bind to T-cell receptors (TCRs) (see for reference Sims, Stuart et al. “MHC-peptide tetramers for the analysis of antigen-specific T cells. ” Expert review of vaccines vol. 9, 7 (2010): 765-74).T cell cross-reactivity of a MAP as herein described can be assessed using well-known CTL (cytotoxic T lymphocytes) assays in the field (see for example Ying Men et al., Assessment ofImmunogenicity of Human Melan-A Peptide Analogues in HLA-A *02 1 Kb Transgenic Micel. J Immunol 15 March 1999; 162 (6): 3566-3573 or in Colombetti S et al., Impact of Orthologous Melan-A Peptide Immunizations on the Anti-Self Melan-A / HLA-A2 T Cell Cross-Reactivity 1. J Immunol 1 June 2006; 176 (11): 6560-6567). Briefly, cells (typically from a tumor cell line) expressing (endogenous or recombinant expression) both the MHA associated peptide and the matched HLA molecule (typically the cell is recombinantly expressing the human matched allele) are co-cultured with T cells (typically CTLs) specific for the peptide. T cell reactivity (Cytotoxic activity) can be followed by measurement of IFN-y concentration in the supernatant, for example by ELISA (see for example Chapatte L et al., Final Antigenic Melan-A Peptides Produced Directly by the Proteasomes Are Preferentially Selected for Presentation by HLA-A *02 1 in Melanoma Cells!. J Immunol 15 November 2004; 173 (10): 6033-6040).A polypeptide can generally be considered to be immunogenic where it elicits a response which is at least 20%, suitably at least 50% and especially at least 75% (such as at least 90%) of the activity of a reference immunogenic sequence e.g., in an in vitro immunogenicity assay as above described. Reference peptides can be selected from well-established immunogenic peptides from neoantigens, tumor associated antigens (TAAs), such as Melan A peptide, or CTA, as well as CMV or EBV derived peptides.Method for identifying and / or producing a polypeptide of the disclosure.The present disclosure encompasses a method for identifying an MHC associated peptide (MAP) or a polypeptide comprising it as herein disclosed.In some embodiments, the method comprises a step of identifying a transcript as herein defined, notably a transcript derived from the gene NIHCOLE as defined above.Polypeptides of the present disclosure (including MAPs) can be used (notably in immunogenic or vaccine compositions) for the treatment of cancer (either as a therapeutic treatment or prophylactic treatment) as well as for the creating of antigen binding proteins (ABPs), such as antibodies or TCRs to target cancer cells. The polypeptides of the present disclosure are therefore specifically expressed in tumor cells (generally meaning that the antigen is “not-detectably expressed” or non-significantly expressed” in healthy tissues) and / or are differentially expressed (i.e.: overexpressed) in tumor cell or tissues as compared to healthy cells or tissues.The expression level of a given antigen can be assessed at the proteomic and / or at the transcriptomic level according to well-known practices in the field. These assays (including RNA-based and peptide-based assays) are described in detail in the hereinafter section related to the selection and diagnosis methods.For example, comparison of the fold change expression level can be achieved at the transcriptomic level by quantifying the level of expression of nucleic acid transcripts coding for the antigen, or at the peptidomic level, by quantifying the peptide itself.Transcriptomic analysis can be achieved using RNA sequencing data and by quantifying the reads corresponding to the transcript encoding the antigen of interest (for example by using RNA seq data from public libraries and / or from a patient sample, notably a patient tumor sample), by using PCR-based assays, and / or by using hybridization assays (such as typically RNA in situ assays, e.g. FISH assay).Quantification of the peptide expression can be achieved using mass spectrometry-based analysis or antibody-based detection. Quantification methods are detailed below as well as in the results included herein. Transcriptomic and proteomic data can be obtained from collection of public databases.As mentioned above analysis of the antigen expression level can be performed in a patient sample (typically a tumor sample) and / or in a sample collection (typically a public sample collection). Assessment of the expression level of a given antigen in a sample collection can be used to establish expression threshold(s) usable as reference value(s) in diagnosis, prognosis and selection methods described hereinafter.A healthy sample collection can include samples obtained from the same type of healthy tissue (e.g., heart, brain, liver, etc.) or cells, or from different types of healthy tissues or cells. A well-known and broadly used normal tissue sample collection is the Genotype-Tissue Expression (GTEx) database, currently comprising samples from up to 54 non-diseased tissue sites across nearly 1,000 deceased individuals. All individuals have been densely genotyped to assess genetic variation within their genomes by Whole Genome Sequencing (WGS) and Gene expression of each tissue has been assessed by RNA sequencing (bulk RNA-seq).“A tumor sample collection” as used herein can include samples from e.g., the same type of organ, tissue, or cell. Typically, a sample collection can include at least 30 samples; notably at least 50 samples, at least 100; at least 500 or at least 1000 or more samples from at least 10; notably at least 30; at least 50; at least 100; at least 500; at least 1000 or more patients. Well-known tumor sample collections include the database of the TCGA (The Cancer Genome Atlas) cancer genomic program, issued by a joint effort between NCI and the National Human Genome Research Institute landmark cancer genomics program, that molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types; and the CCLE (Cancer Cell Line Encyclopedia) database that provides genetic and pharmacologic characterization of a large panel of human cancer cell lines.In some embodiments, a disease specific, in particular the tumor specific antigen (i.e. target polypeptide, including target MAP) is encoded by a transcript or a nucleic acid sequence that is expressed in one or more cell or tumor sample with at least 1.5 log 2 fold change, at least 1.75-, at least 2-, at least 3-, at least 4- or at least 5 log 2 fold change as compared to its expression level in one or more corresponding normal (i.e. healthy) cell or sample.In some embodiments, the tumor specific antigen is preferentially expressed in one or more cell or tumor sample at an expression level that is at least 2-, at least 3-, at least 4-, at least 5, at least 6-, at least 7 or at least 8- times, 9- times, 10-times, 15-times, 20-times, 50-times or 100-times higher than its expression level in one or more corresponding normal (i.e. healthy) cell or sample.It has notably been shown (see results included herein) that NIHCOLE transcripts, notably transcripts encoding the P12 junction as per the present disclosure are highly differentially expressed in tumor tissues as compared to normal tissues. In particular expression of NIHCOLE transcripts is nearly detectable in most types of healthy tissues, including tissues that are particularly at risk for tumor toxicity such as brain , heart, liver, lung, gastro-intestinal tissues, etc.Typically, an antigen that is specifically expressed in tumor tissues is further expressed in more than 5 %, notably more than 10 %, and typically more than 15 % of tumor samples obtained from a tumor sample collection (including cell and tissue collections). In some embodiments, a tumor specific transcript or antigen is preferably expressed in less than 20 %, notably less than 10 %, less than 5 % or less than 1 % of the normal (i.e. healthy) tissue samples or cells obtained from a sample (tissue or cell) collection (also named herein dataset).Ideally, a tumor antigen according to the present disclosure is shared among individuals. Typically, a shared antigen is expressed (i.e. at the transcriptomic or at the proteomic level) in more than 10 %, notably more than 15 %, more than 20 %, more than 25 %, more than 30 %, more than 35%, more than 40 %, more than 45 %, more than 50 %, more than 60 %, more than 70 %, more than 80 %, more than 85 %, more than 90 % or more than 95 % of tumor patient, in tumor tissues notably of patients suffering from a solid tumor as previously defined.In some embodiments, the method of the present disclosure for identifying a target polypeptide comprises a step of identifying the open reading frame (ORF) sequences from the identified transcripts. In some embodiments, the transcript is then in silico translated in six frame translations (both forward and reverse direction), notably into 3 frame translation by using the same strand as the one encoding the peptide of interest (typically the strand coding for the gene NIHCOLE), and the resulting amino-acid sequences are then fragmented at all stop codons.In some embodiments, a library comprising the identified peptide sequences is assembled.In some embodiments, the method for identifying a tumor antigen as per the present disclosure comprises a step of identifying and / or selecting epitopes (e.g. MAPs) or peptides from an ORF as above mentioned, or from a peptide library, which bind an MHC molecule with an affinity of at least 10'6M as previously defined. MHC binding affinity can be assessed as previously described using in silico prediction and / or in vitro assays.In some embodiments, the method for identifying a tumor antigen as per the present disclosure comprises a step of identifying peptides that are present in the MHC ligandome (typically the MHC I ligandome) of tumor cell samples, notably cells from solid tumor tissues, notably from gastrointestinal cancers or tumor, lung tumor or cancer cand / or ovarian cancer or tumor . This step allows the non-ambiguous identification of peptides that are presented by MHC I molecules.Such identification can be achieved through a proteogenomic approach, wherein mass spectrometry (MS)-based proteomics (and notably immunoproteomics) data are matched against the peptide’s library are searched against immunopeptidomic MS / MS spectra (obtained from a tissue samples or cells including cell lines such as tumor samples and tumor cells, in particular tumor samples or cell lines).The MHC-ligandome is thus typically in the form of raw mass spectrometry (MS) data (z. e. : spectra) obtained in MS-based proteomics (notably immunoproteomics) techniques such as bottom-up proteomics (shot-gun proteomics) and top-down proteomics from one or more tissue samples or cells (e.g.: tumor samples and tumor cells).The immunopeptidomic approach is typically based on immunoaffmity purification (IP) of HLA / MHC complexes typically from mild detergent solubilized lysates, followed by extraction of the HLA / MHC peptides (HLA / MHCp). The extracted peptides can be then separated by chromatography and directly injected into a mass spectrometer. The tumor MHC / HLA-ligandome is typically obtained by first purifying surface MHC -bound (i.e., HLA-I or HLA-2 molecules) peptides followed by their amino acid sequence characterisation. Typically, the MHC / HLA ligandome is obtained from tumor cells (such as cells from solid tumors, notably tumor or cancer from the digestive system, the lung, the liver, the ovaries, the uterus or the pancreas) from one or more tumor samples (e.g., biopsy or tissue) or tumor cell lines. For example, MHC / HLA-bound molecules can be purified by immunoprecipitation from the cell lysate, using an antibody specific to the desired MHC / HLA species (e.g., using MHC / HLA-IP). MHC / HLA-associated peptides can be separated from the larger MHC / HLA components and the peptide fraction can be further analysed by LC tandem mass spectrometry (LC-MS / MS). The peptide sequences can be identified by spectral interpretation. The large-scale data acquired from high-resolution mass spectrometers are typically interpreted using algorithms that enable assignment of mass spectra to amino acid sequences.A variety of software is available to the skilled person for interpretation of MS fragment spectra (see for example Purcell, A.W., Ramarathinam, S.H. & Ternette, N. Mass spectrometry-based identification of MHC-bound peptides for immunopeptidomics. NatProtoc 14, 1687-1707 (2019) or Prianichnikov, Nikita et al. “MaxQuant Software for Ion Mobility Enhanced Shotgun Proteomics. ” Molecular & cellular proteomics: MCP vol. 19,6 (2020): 1058-1069). MS-based immunopeptidomic are also well detailed in Forlani, Greta et al. MCP, vol. 20 100032. 6 Jan.2021; as well as Chong, Chloe et al. “High-throughput and Sensitive Immunopeptidomics Platform Reveals Profound Interferony-Mediated Remodeling of the Human Leukocyte Antigen (HLA) Ligandome.” Molecular & cellular proteomics: MCP vol. 17,3 (2018): 533-548, which refers to the use of MaxQuant computational proteomics platform to search the peak lists against the UniProt databases - see Cox, Jurgen, and Matthias Mann. Nature biotechnology vol. 26,12 (2008): 1367-72.). Additional references which describe well-suited protocols for obtention of MS raw data usable according to the present disclosure are also provided in the results of the present application. According to the method of the present disclosure public MS data can be used as illustrated for example in the results included herein.In some embodiments, the selected peptides can be further filtered against canonical proteins, typically canonical proteins from the human proteome (e.g.: typically obtained from Swiss-Prot and TrEMBL databases). UniProtKB / TrEMBL is a computer-annotated protein sequence database complementing the UniProtKB / Swiss-Prot Protein Knowledgebase. UniProtKB / TrEMBL contains the translations of all coding sequences (CDS) present in the EMBL / GenBank / DDBJ Nucleotide Sequence Databases and also protein sequences extracted from the literature or submitted to UniProtKB / Swiss-Prot. The database is enriched with automated classification and annotation. In some embodiments, the method for identifying a tumor antigen as per the present disclosure comprises a step of searching peptides from the peptide library in the MHC ligandome from normal healthy cells.Public MHC ligandome libraries (obtained from healthy or tumor tissues or cells samples) can be used according to the present disclosure (examples and references are provided in the results included herein).In some embodiments the method comprises a step of assessing immunogenicity of a peptide according to the present disclosure. Assessment of immunogenicity can be achieved as described and exemplified in the prior section. In some embodiments, the immunogenicity of a selected peptide can also be assessed using the BamQuery pipeline as described in Cuevas, Maria Virginia Ruiz et al. “BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens. ” Genome biology vol. 24,1 188. 15 Aug. 2023.In some embodiments, the method comprises a step of assessing the putative on target of tumor toxicity of a given polypeptide (typically a MAP). This typically comprises the analysis of the genomic origin and / or the one or more transcriptomic sequence (s) coding for the said peptide. In some embodiments, all putative alternative regions coding for a selected peptide, are retrieved by translating the peptide sequence in all (3 if only the same strand as the given peptides is considered or 6 if the strand origin is not considered) frames and searched in the refence genome (hgl 9 and hg38). This step can be achieved using public tools such as BLAST, (see Gertz, E.M., Yu, YK., Agarwala, R. et al. Composition-based statistics and translated nucleotide searches: Improving the TBLASTN module of BLAST . BMC Biol 4, 41 (2006)). Typically, a peptide that is encoded by less than 10, less than 9, less than 8, less than 7, less than 7, less than 6, less than 5, less than 4, less than 3 different (contiguous) genomic regions is selected. Preferably the selected polypeptide (including MAPs) is encoded by no more than 2 different genomic regions, is encoded by a single contiguous genomic region or is not encoded by a contiguous genomic sequence (the latter is typically the case for peptide arising for a splice transcript which arises from 2 noncontiguous genomic regions). Preferably the peptide is selected if it is encoded by a transcript having no more than 5, no more than 4, no more than 3, no more than 2 different genomic origins, notably a single genomic origin, or having no contiguous genomic origin.In some embodiments, all alternative putative transcripts coding for the identified polypeptide (including MAPs) are searched among the human transcriptome (public libraries can be used as mentioned herein as well as illustrated in the examples herein, typically the GTEx cohorts are used). The transcriptome can include the annotated transcriptome (e.g., in hg 19 or in hg38) as well as the non-canonical and / or non-annotated transcriptome (typically reconstructed transcripts). Typically, a peptide is selected when is encoded by a transcript having less than 50, notably less than 40, less than 30, less than 20, less than 15, less than 10, less than 9, less than 8, less than 7, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2 different contiguous genomic origins, or only one contiguous genomic origin. The one or more transcripts encoding the peptide are typically checked for their expression in normal versus in normal tissues or cells.A polypeptide as per the present disclosure may be recombinantly produced by expression in a host cell comprising a nucleic acid encoding it (recombinant expression) or by chemical synthesis (e.g., solid- phase peptide synthesis).Polypeptides as per the present disclosure can also be readily synthesized by manual and / or automated solid phase procedures well known in the art. Suitable syntheses can be performed, for example by utilizing "T-boc" or "Fmoc" procedures. Techniques and procedures for solid phase synthesis are described in for example Solid Phase Peptide Synthesis: A Practical Approach, by E. Atherton and R. C. Sheppard, published by IRE, Oxford University Press, 1989. Alternatively, theMiHA peptides may be prepared by way of segment condensation, as described, for example, in Liu et ai., Tetrahedron Lett. 37: 933-936, 1996; Baca et ai., J. Am. Chem. Soc. 117: 1881-1887, 1995; Tam, Int. J. Peptide Protein Res. 45: 209-216, 1995; Schnolzerand Kent, Science 256: 221-225, 1992; Liu and Tam, J. Am. Chem. Soc. 116: 4149-4153, 1994; Liu and Tam, Proc. Natl. Acad. Sci. USA 91 : 6584-6588, 1994; and Yamashiro and Li, Int. J. Peptide Protein Res. 31 : 322- 334, 1988. Other methods useful for synthesizing a polypeptide are described in Nakagawa et al., J. Am. Chem. Soc. 107: 7087-7092, 1985.Therefore, embodiments of the present disclosure encompass a non-naturally occurring polypeptide wherein said peptide consists or consists essentially of an amino acid sequences defined herein and has been synthetically produced (e.g. synthesized) as a pharmaceutically acceptable salt. The salts of the peptides according to the present disclosure differ substantially from the peptides in their state(s) in vivo, as the peptides as generated in vivo are no salts. The non-natural salt form of the peptide may modulate the solubility of the peptide, in particular in the context of pharmaceutical compositions comprising the peptides, e.g. the peptide vaccines as disclosed herein. Preferably, salts are pharmaceutically acceptable salts of the peptides.In some embodiments, the herein-mentioned polypeptide is substantially pure. A compound is "substantially pure" when it is separated from the components that naturally accompany it. Typically, a compound is substantially pure when it is at least 60%, more generally 75%, 80% or 85%, preferably over 90% and more preferably over 95%, by weight, of the total material in a sample. Thus, for example, a polypeptide that is chemically synthesized or produced by recombinant technology will generally be substantially free from its naturally associated components, e.g. components of its source macromolecule. A nucleic acid molecule is substantially pure when it is not immediately contiguous with (i.e., covalently linked to) the coding sequences with which it is normally contiguous in the naturally occurring genome of the organism from which the nucleic acid is derived. A substantially pure compound can be obtained, for example, by extraction from a natural source; by expression of a recombinant nucleic acid molecule encoding a peptide compound; or by chemical synthesis. Purity can be measured using any appropriate method such as column chromatography, gel electrophoresis, HPLC, etc. In some embodiments, the polypeptide is in solution. In another embodiment, the polypeptide is in solid form, e.g., lyophilized. Peptide MHC complexes and uses thereof.The present disclosure also encompasses a pMHC molecular complex (also shortly named herein molecular complex) comprising a MAP (MHC associated peptide) as herein defined (such as a peptide derived from the sequences of table 3, fragments and variants thereof or a peptide of Table 9 or 10 or a variant thereof) and an HLA type I molecule as previously defined. A pMHC complexcomprising a MAP and an MHC molecule is also named a pMHC monomer (or MHC -peptide monomer). Typically, the MHC associated peptide binds the MHC molecule with a binding affinity of at least 10'6M as detailed in the previous section.Typically, as herein intended, an MHC type I molecule comprises an MHC I a-chain and a P-2 microglobulin chain. MHC I a-chain comprises -chain from HLA-A, -B, and -C allotypes, notably from HLA-A supertypes (e.g., A01, A01A03, A01A24, A02, A03, A24) and HLA-B supertypes (e.g., B07, B08, B27, B44, B58, and B62). In preferred embodiments the a-chain is selected from a-chain of the following alleles: A*02:01; A*24:02; A*01:01; A*03:01; A*ll:01; A*33:03; C*04:01; C*01:02; C*02:02; C*03:03; C*03:04; C*06:02; C*07:01; C*07:02; C*12:03; B*15:01; B*35:01; B*40:01; B*40:02; B*44:03; B*51:01; and B*52:01.In some embodiment, the MHC molecule is mutated. For example, the HLA molecule (typically the alpha chain) can comprise one or more amino acid mutation(s) known to reduce the CD8-HLA interaction.In some embodiments, the molecular complex comprises a peptide of SEQ ID NO: 1034 or a variant thereof as previously defined and an MHC molecule from the A* 03 supertype, notably an MHC A*03:01 or an MHC A*ll:01 molecule.In some embodiments, the molecular complex comprises a peptide of SEQ ID NO: 1064 or a variant thereof as previously defined and an MHC molecule from the A* 03 supertype, notably an MHC A*03:01 or an MHC A*ll:01 molecule.In some embodiments, the molecular complex comprises a peptide of SEQ ID NO: 1089 or a variant thereof as previously defined and an MHC molecule from the A* 02 supertype, notably an MHC A*02:02 molecule.In some embodiments, the molecular complex comprises a peptide of SEQ ID NO: 1101 or a variant thereof as previously defined and an MHC molecule from the A* 02 supertype, notably an MHC A*02:02 molecule.In some embodiments, the molecular complex comprises a peptide of SEQ ID NO: 1131 or a variant thereof as previously defined and an MHC molecule from the A* 02 supertype, notably an MHC A*02:02 molecule.In some embodiments, apeptide-MHC molecular complex of the present disclosure comprises more than one MHC I molecule notably at least 2-, 3-, 4- or more MHC I molecules. Each MHC molecule can bind (or load) one MAP.In some embodiments, the MHC molecule(s) and / or the peptide can be labeled, e.g. with one or more fluorescent dyes notably allowing detection in flow cytometer, quantum dots, or enzymaticlabels (such as biotin-based labels, HRP, or Alkaline Phosphatase ) for use notably in microscopy or plate-based detection assays.MHC polypeptides (the a-chain and the P-2 microglobulin chain) can be linked by non-covalent and / or covalent bond(s) (including peptide bonds).In some embodiments, the peptide-MHC complex is multimerized. Accordingly, in some aspects, the present disclosure provides a multimer of MHC molecules loaded with or covalently attached to a herein disclosed peptide. The MHC molecules can be bonds through electrostatic and / or covalent bonds. Such multimers may be attached to a tag, for example a fluorescent tag, which allows the detection of the multimers. A great number of strategies have been developed for the production of MHC multimers, including MHC dimers, tetramers, pentamers, octamers, etc. (reviewed in Bakker and Schumacher, Current Opinion in Immunology 2005, 17:428-433).In some embodiments, the MHC molecule can be biotinylated. Addition of streptavidin that has several biotin-binding sites can be used to produce pMHC tetramers (i.e. comprising 4 MHC-peptide monomers). Typically, the streptavidin can be labeled with fluorescent or enzymatic labels. The peptide can be bound to the MHC molecule through non-covalent interactions and / or covalent bonds. Preferably the peptide is loaded through non-covalent bonds on the MHC binding groove. Typical non-covalent bonds or interactions involve hydrogen bonds, hydrophobic interactions and Van der Waals forces. In another embodiment, the peptide is covalently attached / bound to the MHC molecule (typically to the alpha chain). In such a construct, the peptide and the MHC molecule (typically the alpha chain) are produced as a synthetic fusion protein, typically with a short (e.g., 5 to 20 residues, preferably about 8-12, e.g., 10) flexible linker or spacer (e.g., a polyglycine linker). The present disclosure therefore also encompasses a nucleic acid encoding a fusion protein comprising a peptide as defined herein fused to an MHC molecule (typically the alpha chain). Typically, the MHC molecule is a recombinant molecule (i.e. the a-chain and the P-2 microglobulin chain are recombinantly produced).Typically, the MAP is a recombinant or synthetic peptide.Peptide-MHC monomers or polymers (including tetramers) typically biotinylated or labeled with a fluorophore can be used soluble in various assays (i.e. ELISA, SPR, BLI, or flow cytometry) to assess binding to a binding protein (e.g. a TCR, a TCR like or an antibody based binding protein) or to screen a binding protein.In some embodiments, the peptide-MHC molecular complex of the present disclosure is attached (typically covalently fixed) on a support. Typical supports according to the present disclosure include, but are not limited to, beads, plates or chips.Typically, the molecular complex can be labeled as above described, wherein the peptide and / or the MHC molecule is labeled.A molecular complex, typically wherein the peptide is loaded to the MHC molecule can be attached to solid beads. Such complex can therefore be used in flow cytometry assay or T-cell stimulation assay as herein described. For example, MHC tetramers loaded can be attached on magnetic of polystyrene beads and typically labeled using fluorophores for flow cytometry sorting. Such complexes can be used for T cell isolation or activation assays. As mentioned above such functional assays can be used to assess binding of the molecular complex to a binding protein. Molecular complexes coated on magnetic beads can be used for sorting antigen-specific T cells via magnetic separation.A peptide-MHC complex can also be immobilized on a plate, typically an ELISA plates for use notably in high-throughput screenings (such as in T cell-activation assay, MHC -peptide binding assays or binding protein assays).A peptide-MHC complex can also be immobilized on sensor chips (typically SPR or BLI sensor chips). Such functionalized chips can be used in various assays to assess specificity and affinity of a binding protein (including a TCR or an antibody-based binding protein) or to measure peptide-MHC stability and affinity, for peptide or binding protein screening.In some embodiments, the peptide can be recombinantly expressed in a cell line expressing the matched MHC molecule. Typically, the matched MHC molecule is recombinantly expressed. In some embodiments, the cell line is a monoallelic cell line.In some embodiments, the molecular complex can be conjugated to a carrier polypeptide or protein (such as KLH, OVA or classical scaffold proteins).In some embodiments, the molecular complex can be displayed on particles such as liposomes or nanoparticles.Molecular complexes as defined above and according to the present disclosure can be used in specificity and potency assays to assess binding (affinity and cross-reactivity) and functionality of a binding protein targeting a molecular complex of the present disclosure. As described in the present application, such assays involve in a non-limitative manner, binding assays (e.g. ELISA, SPR, BLI, etc.), including functional specificity assays (e.g. FACS, western blot, immune-histochemistry, etc.) and cross-reactivity screenings (involving e.g. previously mentioned assays such as ELISA but also typically protein arrays and cell panels), and epitope mapping and validation (e.g. competition assays and mass-spectrometry-based epitope mapping). Potency and efficacy of the binding protein is typically assessed with cell-based assays comprising, but not limited to, T cellactivation assays, and / or CTL assays (e.g. FACS). Such assays are typically used in QC (quality control) of antigen binding protein to be used in clinic.Molecular complex as defined above can also be used in the production and / or screening of antigen binding proteins (see notably the section related to antigen binding proteins of the present disclosure and method for screening thereof).Antigen binding molecules and methods for identifying or producing thereof.Another aspect of the disclosure relates to an antigen binding molecule, which specifically binds to a target antigen (i.e. a polypeptide and notably a MAP as herein defined). Typically the antigen is a complex antigen consisting in a molecular complex comprising a target MAP in combination with an MHC I molecule as herein described.As per the present disclosure antigen binding molecules include antigen binding protein (which typically includes antibody-based and TCR-based binders, affimers, and synthetic peptides), nucleic acid-based ligands (e.g. aptamers), and small molecules or molecular imprinted polymers. Nucleic acid ligands are mostly represented by aptamers (see e.g. Ruscito A, DeRosa MC. Small-Molecule Binding Aptamers: Selection Strategies, Characterization, and Applications. Front Chem.2016,4:14 and Kelly, L., Maier, K.E., Yan, A. etal. A comparative analysis of cell surface targeting aptamers. Nat Commun 12, 6275 (2021)) and consist in short single stranded DNA or RNA molecules that can fold into 3D structures to bind with high specificity to targets (including antigenic peptide targets). Aptamers are raised interest as they can be easily chemically synthesized and can have specificity and affinity values that are equivalent to antibodies.Affimers (see e.g. Skrlec K, Strukelj B, Berlec A. Non-immunoglobulin scaffolds: a focus on their targets. Trends Biotechnol. 2015 ,33(7) .408-418; Gebauer M, Skerra A. Engineered protein scaffolds as next-generation therapeutics. Annu Rev Pharmacol Toxicol (2020) 60: 391-415; Tans R, van Rijswijck DMH, Davidson A, et al. Affimers as an alternative to antibodies for protein biomarker enrichment. Protein Expr Purif. 2020; 174: 105677) are typically engineered protein scaffolds that bind to specific antigen and are generally derived from human proteins scaffolds such as e.g. cystatin, or ankyrin repeats. Affimers can be of high relevance due to their small size and great tissue penetration. They are generally chemically stable and can be produced easily in bacteria, without batch-to-batch variation.Synthetic short peptides mimicking antibody binding sites can also be used as they can be customized for high specificity and can be highly stable.Molecular imprinted polymers (MIPs) are synthetic polymers designed with cavities that mimic natural binding sites. They can be highly stable and easily synthesized.Further details and embodiments regarding binding molecules are provided below with regard to antigen binding proteins (ABPs) as a generic binder for seek of clarity. It is, however, intended herein that the present disclosure is not limited to binding protein and includes more generally all binding molecules. In particular, affinity and specificity (including cross reactivity) can be assessed in similar assays, and binding molecules as above mentioned, are suitable for use in various therapeutic applications as herein described. For example, CD3 aptamers and TCE including thereof as well as aptamer-functionalized CAR have been described in the literature with promising results (e.g. Mamet N, et al, Commun Biol 2020.https: / / doi.org / 10.1136 / jitc-2021-SITC2021.788; Menon, Ashwathi Puravankara et al. “CD3 aptamers promote expansion and persistence of tumor-reactive T cells for adoptive T cell therapy in cancer. ’’Molecular therapy. Nucleic acids vol. 35,2102198.23 Apr. 2024, doi: 10.1016f.omtn.2024.102198; Zhang, Qiang et al. “Aptamer-Based Nongenetic Reprogramming of CARs Enables Flexible Modulation of T Cell-Mediated Tumor Immunotherapy. ’’ACS central science vol. 10,4813-822. 21 Mar. 2024).Functional characteristics of an ABP of the present disclosureThe following criteria are typically estimated for the screening of a binding molecule directed against a target antigen:the specificity (i.e., the ability to bind the target antigen with a sufficient affinity according to the definition provided below), and that support notably the efficacy of the binding molecule. Binding affinity can be assessed using in vitro assays as detailed below. Efficacy (or potency) of a binding molecule can be assessed using in vitro assays such as killing assays (CTL assays), T cell activation assay and / or can be assessed in vivo by assessing tumor survival as also described below.the selectivity (i.e. the ability to bind specifically the target antigen over other antigens). Selectivity can be assessed as detailed below by cross reactivity analysis of the binding molecule, typically into competition assays comprising a combination of the target antigen and one or more non-target (similar or counter-selection) antigen(s). Assessment of selectivity allows to estimate potential off-target binding and the associated risk of toxicity. Several techniques are typically used to assess cross reactivity (see also the techniques used to support the Investigational New Drug applications [G] for antibodies or TCRs as mentioned in Klebanoff CA, Chandran SS, Baker BM, Quezada SA, Ribas A. T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. Nat Rev Drug Discov. 2023;22(12):996-1017).Typically, the present disclosure encompasses binding molecules, notably binding proteins such as (but not limited to) antibodies, fragments and variants thereof, or T cell receptors (TCRs) that specifically bind a peptide or a polypeptide as herein disclosed (including variant thereof), typically in associated with an MHC class I molecule. More particularly, the present disclosure encompassesa binding molecule, notably a binding protein that specifically binds a molecular complex (i.e. a peptide-MHC complex) as previously described. In the following description in the absence of specification it is intended that the target antigen is a molecular complex as previously defined. Non-target antigens (also named off-target antigens), typically used in competition and / or cross reactivity assays typically include molecular complex comprising a similar or non-relevant peptide and an MHC molecule that can be the same as the MHC molecule of the antigen molecular complex or different.Typically, the ABP comprises an antibody, a T cell receptor (TCR), an antigen-binding fragment or variant thereof (including scFv and scFv-like TCRs). According to the present application, an antigen binding protein has herein described can thus be implemented into various therapeutic modalities or format which include in a non-limitative manner: immune cell engagers (ICEs), antibody drug conjugates (ADCs), chimeric receptor such as chimeric antigen receptors (CARs) and T cell receptors (TCRs - including chimeric TCRs and TCR binding fragments).A “specific binding” with regard to an antigen binding protein as herein intended typically means that the antigen binding protein binds the target molecular complex with a binding affinity as defined by Kd, of 500 pM or less, notably of 1 pM or less; of 50 nM or less, of 10 nM or less, of 1 nM or less, or of 100 pM or less.Well-suited methods for assessing specificity and selectivity of a binding molecule, typically a binding protein (such as an antibody, a TCR, a fragment or a variant thereof) have been previously described notably in the section related to the assessment of peptide-MHC binding and are further detailed below.A variety of immunoassay formats may be used to select antigen binding molecules (e.g., binding proteins) specifically immunoreactive (selective) for a molecular complex as herein described. Typically, assay-specific validation should confirm that the antigen binding protein is specific for its target antigen and notably that it selectively binds a molecular complex as herein defined in the presence of other non-target antigens (e.g. non target molecular complexes comprising a similar peptide in association with the same HLA molecule as the target molecular complex or a different HLA molecule). Widely used quantitative assay formats to enable target-specific capture and detection of binding properties include flow cytometry and more generally ligand-binding immunoassay setups.Immunoassays are analytical methods based on signal responses generated as a result of a binding protein-antigen reaction. The readout signal can be generated from a label (e.g. enzymatic, fluorescent, luminescent or radio-isotopic) attached to either the analyte (ligand or antigen) or to the binding protein, or from a secondary, high affinity binding reaction, usually involving anotherlabeled binding protein or the well-characterized biotin-avidin system. Typical validation assays include (in a non-limitative manner):ELISA immunoassays (mostly in solid phase) that are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity). In some embodiments, enzyme-linked immunosorbent assays (ELISA) are used to support detection of various antibodies or antigens that are present within a sample by forming an enzyme triggered color change.Radioimmunoassay (RIA) which allows detection of antibody - antigen complexes using radioisotopes. This in vitro assay usually offers high sensitivity and high specificity (even in minute concentrations). RIA is based on the competitive assay method and usually uses a gammaradioactive isotopes of iodine that is known as Iodine-125 (125-1) to label the antigen, which can be prepared with high specific activity and offers 100% isotopic abundance. The unlabeled antigens from the serum compete with the radioactive antigens for the antibody binding sites. As the quantity of unlabeled antigens increases, more radiolabeled antigens are displaced from the antibody - which results in reducing the ratio of antibody-bound radiolabeled antigen to free radiolabeled antigen. Bound antigens are then separated out and the radiolabeled free antigens within the supernatant can be detected using a gamma counter a scintillation counter or by autoradiography (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein).Western Blot assays, wherein the antigen is detected in a sample via initial size separation and then blotting on to a membrane to be visualized by an antibody; see as an example reference Pillai-Kastoori, Lakshmi et al. “Antibody validation for Western blot: By the user, for the user. ” The Journal of biological chemistry vol. 295,4 (2020): 926-939),Immunoprecipitation (IP)-based assays, where protein complexes are immunoprecipitated from cell lysate. Enrichment of target protein through IP can be combined with detection methods such as western blot or mass spectrometry (IP-MS) (see for references Marcon E et al. Nat. Methods 12, 725 731 (2015); or Fredolini, C., Bystrom, S., Sanchez-Rivera, L. etal. Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles. Sci Rep 9, 8324 (2019)).Immunohistochemistry (IHC) and immunocytochemistry (ICC) typically used to determine whether an antigen binding protein recognizes the correct protein or polypeptide based on cellular and subcellular (e.g. plasma membrane) localizations.Flow cytometry (FACS) analysis which is typically used to measure binding specificity and selectivity of antigen binding proteins in a cellular context, information that is not captured in atraditional SPR or ELISA-based binding assay. Flow cytometry is a fluidics and optics-based method that evaluates fluorescently labeled cell suspensions in a single cell flow to capture receptor-or antigen-binding events in intact cells. Typically, the apparent affinity-binding constant value (KD) of an antigen binding protein as herein described for molecular complex as previously defined can be assessed using flow cytometry by measuring the saturation curve of the binding protein to said antigen and by determination of the EC 50 value. As flow cytometric analysis of antibody binding is an indirect measurement of kinetic values, it can be used in combination with SPR analysis to provide kinetic data for the studied antibodies. As a matter of example, binding (EC50) of an antigen binding protein directed to the molecular complex as herein described to a cell line (typically a tumor cell line) expressing (naturally or recombinantly expressing or overexpressing said antigen can be assessed by measuring the mean fluorescence intensity using flow cytometry (e.g., FACSVerse, FACSymphony or BD LSRII) via a secondary antibody, (e.g., F(ab’)2 a-human IgG Fc or Streptavidin (BD Pharmingen) and analyzed using typically FlowJo software (RRID:SCR_008520). To determine the number of antigens on the cell surface (measured as antibodies per cell (ABC)), BD Quantibright Beads can be used. The standardized beads typically comprise four known values of PE to calibrate the FL2 axis and were used in conjunction with PE-bound mAb specific for the target antigen.High-throughput methods are widely used as they allow to test the specificity of a binding protein against hundred polypeptides at one time. Well-known assays include typically peptide arrays and dot blots. In peptide array, antibody binding events are detected by first spotting arrays with the peptides / proteins and then adding the antibody (similar to ELISA). Dot blot principle is similar to peptide array and comprises serial dilutions of several peptides or polypeptides that are plotted onto nitrocellulose and used to check the specificity of the antigen binding protein of interest against these control peptides / polypeptides). Other methods amenable for high-throughput screening include IP-MS assays previously mentioned as well as kinetic exclusion assays (e.g., KinExA, see Darling RJ, Brault P-A. Kinetic exclusion assay technology: characterization of molecular interactions. Assay Drug Dev Technol. 2004,2:647- -57 and Rathanaswami P, Richmond K, Manchulenko K, Foltz IN. Kinetic analysis of unpurified native antigens available in very low quantities and concentrations. Anal Biochem. 2017; 414:7-13; but see also Haenel C, SatzgerM, Ducata DD, Ostendorp R, Brocks B. Characterization of high-affinity antibodies by electrochemiluminescence-based equilibrium titration. Anal Biochem. 2005,339: 182-4; as well as1Salimi-Moosavi H, Rathanaswami P, Rajendran S, Toupikov M, Hill J. Rapid affinity measurement of protein-protein interactions in a microfluidic platform. Anal Biochem. 2012,426: 134-41). Kinetic exclusion assay provides an assessment of free ligand at equilibrium, rather than measuring real-time association and dissociation rates to determine affinity. With tight binding antibodies (low or sub pM), KDmeasurements need to be made at these very low sample concentrations. KinExAcan be used to make quantitative measurements at these low concentrations therefore allowing for accurate KD measurements for those very tight binders. Kinetic exclusion assays are also well-suited for measuring binding to cell membrane proteins on intact whole cell (see for example implementations: Rathanaswami, Palaniswami et al. “High-affinity binding measurements of antibodies to cell-surface-expressed antigens. ’’Analytical biochemistry vol. 373,1 (2008): 52-60; Drake, Andrew W et al. “Characterizing high-affinity antigen / antibody complexes by kinetic- and equilibrium-based methods. ” Analytical biochemistry vol. 328,1 (2004): 35-43; o Rathanaswami, Palaniswami et al. “Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8. ” Biochemical and biophysical research communications vol.334,4 (2005): 1004-13). In competition immunoassays, the Kinetic Exclusion Assay (KinExA) has been shown to prevent competition from interfering, and the measurement sensitivity (sub pM) can take full advantage of extremely tight binding antibodies (see Ohmura N, Lackie S.J., Saiki H.2001. An immunoassay for small analytes with theoretical detection limits. Anal Chem 73: 3392-3399).The above-mentioned assays can be performed as competition assays using for example various versions of the binding domain (which can be labeled or not) or different antigens (including the primary / target molecular complex and off-target antigens), which can be in solution or immobilized on a surface (such as beads or such as membrane). In some embodiments, excess unlabeled antibody can be used to block binding of a labeled version of the same antibody. Alternatively, excess soluble antigen can be used to block antibody binding to target cells for example. Putative cross-reactivity of an antigen binding protein with another antigen can thus be assessed. Indeed, a competitive antigen binding assay or competition assay represents an indirect quantitative measurement of KDobserved in conditions wherein, for example, titration of an off-target antigen inhibits binding of the primary / target molecular complex antigen with the antigen binding protein. Competition assays can be essentially classified as solution competition assay and surface competition assay. For example, the molecular complex can be present in the running buffer (solution competition) or immobilized on a sensor chip surface (surface competition).With regard to the binding of an ABP to a target molecular complex antigen, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” the molecular complex mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a molecular complex and comparing it to binding to a non-target molecule or complex. Specific binding can also be determined by competition with a control molecule or complex that mimics the epitope recognized on the molecular complex. For example, similar peptides can be used in combination with the same HLA molecular as the target molecular complex. In that case, specific binding is indicated if the binding of the ABP to the target molecularcomplex is competitively inhibited by the control molecule. In some aspects, the affinity of a molecular complex ABP for a non-target molecule or complex is less than about 50% of the affinity for the target molecular complex as herein defined. In some aspects, the affinity of a target molecular complex ABP for a non-target molecule or complex is less than about 40% of the affinity for the target molecular complex as herein defined. In some aspects, the affinity of a target molecular complex ABP for a non-target molecule or complex is less than about 30% of the affinity for the target molecular complex as herein defined. In some aspects, the affinity of a target molecular complex ABP for a non-target molecule or complex is less than about 20% of the affinity for the target molecular complex as herein defined. In some aspects, the affinity of a target molecular complex ABP for a non-target molecule or complex is less than about 10% of the affinity for a target molecular complex as herein defined. In some aspects, the affinity of a target molecular complex ABP for a non-target molecule or complex is less than about 1% of the affinity for the target molecular complex as herein defined. In some aspects, the affinity of a target molecular complex ABP for a non-target molecule or complex is less than about 0.1% of the affinity for the target molecular complex as herein defined.When used herein in the context of two or more ABPs, the term “competes with” or “cross-competes with” indicates that the two or more ABPs compete for binding to an antigen. In one exemplary assay, a first antigen is coated on a surface and contacted with a first ABP, after which a second ABP is added. In another exemplary assay, a first ABP is coated on a surface and contacted with an antigen, and then a second ABP is added. If the presence of the first ABP reduces binding of the second ABP, in either assay, then the ABPs compete with each other. The term “competes with” also includes combinations of ABPs where one ABP reduces binding of another ABP, but where no competition is observed when the ABPs are added in the reverse order. However, in some embodiments, the first and second ABPs inhibit binding of each other, regardless of the order in which they are added. In some embodiments, one ABP reduces binding of another ABP to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. A skilled artisan can select the concentrations of the ABPs used in the competition assays based on the affinities of the ABPs for the antigen and the valency of the ABPs. The assays described in this definition are illustrative, and a skilled artisan can utilize any suitable assay to determine if ABPs compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods, ” in Assay Guidance Manual [Internet], Updated December 24, 2014 (www.ncbi.nlm.nih.gov / books / NBK92434 / ; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; andFinco etal., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety.Assays as previously described are also usually performed using positive and negative controls, and preferably genetic controls, independent-epitope / antibody strategies, testing of multiple cell lines,proteomic approaches, additional evaluation of phospho-specific antibodies, and orthogonal or complementary methods.The affinity / specificity and selectivity of the antigen binding protein can be assessed in comparison to one or more negative controls (i.e., a cell line or tissue sample that does not express the target molecular complex) or positive controls (e.g. a cell line known to present or engineered to present at its cell surface a molecular complex as herein defined, or an antigen presenting cell loaded with a MAP as herein defined, and expressing at it surface the matched MHC molecule). In some embodiments, specificity can be by using engineered cell lines wherein the nucleic acid sequence expressing the peptide and / or the MHC molecule of the target molecular complex has been removed typically by knockout (KO) using for example Crispr / Cas9, or transient gene knockdown (KD) using for example siRNA or shRNA. The absence of positive signal therefore provides a well-accepted standard for negative control.A well-known technique to define a binding molecule cross-reactivity potential is termed amino acid positional scanning (or XR scanning) and comprises establishing which peptide residues form critical contacts with the receptor. In this approach, each amino acid in the cognate peptide of the peptide MHC complex is sequentially replaced with another amino acid. In some embodiments an alanine scan is used wherein an alanine residue, the smallest chiral amino acid is used. An alternative compact amino acid residue, such as glycine, can be used in cases in which the native residue is alanine. The recognition motif of a binding molecule is generally defined by peptide positions in which an amino acid substitution results in significant loss of function (typically >50%) compared with the native amino acid (see also the alanine scanning analysis performed in the results of the Examples in order to identify binder’s footprint (i.e. amino acid residues ensuring binding specificity and selectivity).In some embodiments, assessment of the antibody binding of independent antibodies can be used as a strategy to improve assay specificity. For example, the desired antibody can be compared with a second antibody having one or more different CDRs (notably a different CDR3 sequence). Recombinant antibodies are particularly good for this strategy because they offer high batch-to-batch consistency, reliable ongoing supply, and high specificity.In some embodiments, the target molecular complex can be expressed with a fusion tag to enable the determination of antibody specificity by comparing the signal from the antibody to the tagspecific signal. Broadly used examples include using an affinity tag such as c-Myc or His for biochemical assays or a fluorescence tag like green fluorescence protein (GFP) for microscopy or flow cytometry.Labeled reagents used in the above-mentioned assays to detect the presence of protein-antibody complexes of particular interest can include the following:a. For microscopy, the labeled reagent (e.g., an antibody, or an Fv) can be either directly conjugated to a fluorophore or recognized by a fluorophore-conjugated secondary antibody directed against the labeled reagent. Non-limiting examples of fluorophores, also called fluorescent dyes, include derivatives of cyanine (e.g. Cy3) or rhodamine (e.g., TRITC) or fluorescein (e.g., FITC). b. In certain embodiments, the extracellular antigen-binding domain is labeled with a fluorescent marker. Non-limiting examples of fluorescent markers include green fluorescent protein (GFP), blue fluorescent protein (e.g, EBFP, EBFP2, Azurite, and mKalamal), cyan fluorescent protein (e.g, ECFP, Cerulean, and CyPet), and yellow fluorescent protein (e.g, YFP, Citrine, Venus, and YPet).In some embodiments, the antigen-binding protein binds a molecular complex as previously defined with a dissociation constant (Kd) of about 10'6M or less, 10'7M or less, 10'8M or less, 10'9M or less, IO'10M or less, or 10'11M or less. In some embodiments, the Kd is comprised between about 10'6M and 10'12M, notably between about 10'7M and 10'12M, between about 10'8M and 10'12M, between about 10'7M and 10'11M, between about 10'7M and IO'10M, between about 10'8M and IO'10M, between about 10'8M and 10'12M, between about 10'8M and 10'11M, between about 10'9M and 10'12M, or between about 10'9M and 10'11M. Typically, the KDis comprised between 10'3pM and 50 nM, notably between 0.1 pM and 50 nM, notably between 0.1 pM and 5 nM, or between 1 pM and 10 nM notably between 1 pM and 5 nM, between 10 pM and 5 nM, between 0.1 nM and 50nM or between 0.1 nM and 10 nM, or between 1 nM and 50 nM, notably between 1 nM and 10 nM.In some embodiments, the antigen-binding protein binds to a target molecular complex as previously defined with at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold or more greater affinity than to a non-target molecular complex comprising an off-target peptide and / or an MHC molecule that differs from the MHC molecule of the target molecular complex.In some embodiments, the antigen-binding protein has a Kd for a molecular complex as previously defined, or a polypeptide comprising thereof that is at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold or less than its KDfor a non-target molecular complex comprising an off-target peptide and / or an MHC molecule that differs from the MHC molecule of the target molecular complex.An ABP can bind to each portion of an MHC- peptide molecular complex (i.e., HLA and peptide representing each portion of the complex), which when bound together form a novel target and protein surface for interaction with and binding by the ABP, distinct from a surface presented by the peptide alone or MHC subtype alone. Generally, the novel target and protein surface formed bybinding of an MHC molecule to the MHC-associated peptide does not exist in the absence of each portion of the MHC -peptide complex. In some embodiments, the ABP binds to the MHC- peptide complex antigen through at least one contact point with the MHC molecule and through at least one contact point with the MAP.In some embodiments, the ABP does not bind to the HLA molecule in the absence of the matched HLA-restricted peptide (MAP). In some embodiments, the ABP does not bind the MAP in the absence of the matched HLA molecule. Typically, the ABP binds a molecular complex as herein defined comprising a peptide as herein disclosed in association with a matched MHC molecule when the complex naturally is presented at a cell surface, in particular when the complex is presented at the surface of a tumor cell.As previously defined, the MAP can be non-covalently bound to the MHC molecule or covalently attached / bound to the MHC molecule and typically forms a synthetic fusion protein. In some embodiments, the molecular complex can also be multimerized. The molecular complex may be in solution, expressed at the surface of any suitable target or host cell, including a tumor cell or covalently attached to a solid support (see notably the section related to the description of molecular complex of the present disclosure).The molecular complex antigen used for isolation or creation of the ABPs provided herein may be an intact MHC -peptide complex (also shortly named herein “molecular complex”) or a fragment of an MHC -peptide complex. In some embodiments, the MHC -peptide complex antigen is a non-naturally occurring variant of a naturally- occurring MHC -peptide complex, such as an MHC-peptide complex protein having an amino acid sequence or post-translational modification that does not occur in nature. In some embodiments, the MHC -peptide complex antigen can be truncated by removal of, for example, intracellular or membrane-spanning sequences, or signal sequences. In some embodiments, the MHC -peptide complex antigen is fused at its C-terminus to a human IgGl Fc domain or a poly histidine tag.The present disclosure encompasses an ABP that binds a peptide-MHC molecule complex comprising the MIHI peptide of SEQ ID NO: 1034 or a variant thereof as previously defined in association with an HLA A*03:01 and / or HLA A*ll:01 molecule. Variants of the MIHI peptide include peptides of 8 to 12 amino acids, wherein the isoleucine residue can be replaced by a leucine, and which bind an HLA A*03:01 and / or HLA A* 11:01 molecule with a KD of less than 100 nM as previously defined. Typically, the said ABP does not bind MHC -peptide complexes wherein the MHC molecule is not an HLA A* 03:01 and / or HLA A*11 :01 molecule (irrelevant of the associated peptide and including the MIHI peptide). Typically, the said ABP also does not bind MHC -peptide complexes comprising an HLA A*03 :01 and / or HLA A* 11 :01 molecule and an irrelevant or cross-reactive peptide. By “does not bind” it is also intended low affinity non-specific binding interaction with a Kd in the mM range or more.The present disclosure encompasses an ABP that binds a peptide-MHC molecule complex comprising the MIHI peptide of SEQ ID NO: 1064 or a variant thereof as previously defined in association with an HLA A*03:01 and / or HLA A*ll:01 molecule. Variants of the MIHI peptide include peptides of 8 to 12 amino acids, wherein the isoleucine residue can be replaced by a leucine, and which bind an HLA A*03:01 and / or HLA A*ll:01 molecule with aKD of less than 100 nM as previously defined. Typically, the said ABP does not bind MHC -peptide complexes wherein the MHC molecule is not HLA A*03:01 and / or HLA A* 11:01 molecule (irrelevant of the associated peptide and including the peptide of SEQ ID NO: 1064 peptide). Typically, the said ABP also does not bind MHC -peptide complexes comprising an HLA A*03:01 and / or HLA A* 11:01 molecule and an irrelevant or cross-reactive peptide. By “does not bind” it is also intended low affinity nonspecific binding interaction with a Kd in the mM range or more.The present disclosure encompasses an ABP that binds a peptide-MHC molecule complex comprising the peptide of SEQ ID NO: 1089 or a variant thereof as previously defined in association with an HLA A*02 molecule (notably an HLA A*02:01 molecule). Variants of the this peptide include peptides of 8 to 12 amino acids, wherein one or more of the isoleucine residues can be replaced by a leucine and / or wherein one or more of the leucine residues can be replaced by an isoleucine residue, and which bind an HLA A*02 molecule (notably an HLA A*02:01 molecule) with a KD of less than 100 nM as previously defined. Typically, the said ABP does not bind MHC-peptide complexes when the MHC molecule is not an HLA A* 02 molecule (notably an HLA A*02:01 molecule) (irrelevant of the associated peptide and including the peptide of SEQ ID NO: 1089). Typically, the said ABP does not bind MHC -peptide complexes comprising an HLA A*02 molecule (notably an HLA A*02:01 molecule) and an irrelevant or cross-reactive peptide. The present disclosure encompasses an ABP that binds a peptide-MHC molecule complex comprising the peptide of SEQ ID NO: 1101 or a variant thereof as previously defined in association with an HLA A*02 molecule (notably an HLA A*02:01 molecule). Variants of the this peptide include peptides of 8 to 12 amino acids, wherein one or more of the isoleucine residues can be replaced by a leucine and / or wherein one or more of the leucine residues can be replaced by an isoleucine residue, and which bind an HLA A*02 molecule (notably an HLA A*02:01 molecule) with a KD of less than 100 nM as previously defined. Typically, the said ABP does not bind MHC-peptide complexes when the MHC molecule is not an HLA A* 02 molecule (notably an HLA A*02:01 molecule) (irrelevant of the associated peptide and including the peptide of SEQ ID NO: 1101). Typically, the said ABP does not bind MHC -peptide complexes comprising an HLA A*02 molecule (notably an HLA A*02:01 molecule) and an irrelevant or cross-reactive peptide.The present disclosure encompasses an ABP that binds a peptide-MHC molecule complex comprising the peptide of SEQ ID NO: 1089 or a variant thereof as previously defined in association with an HLA A*02 molecule (notably an HLA A*02:01 molecule). Variants of the this peptide include peptides of 8 to 12 amino acids, wherein one or more of the isoleucine residues can be replaced by a leucine and / or wherein one or more of the leucine residues can be replaced by an isoleucine residue, and which bind an HLA A*02 molecule (notably an HLA A*02:01 molecule) with a KD of less than 100 nM as previously defined. Typically, the said ABP does not bind MHC-peptide complexes when the MHC molecule is not an HLA A* 02 molecule (notably an HLA A*02:01 molecule) (irrelevant of the associated peptide and including the peptide of SEQ ID NO: 1089). Typically, the said ABP does not bind MHC -peptide complexes comprising an HLA A*02 molecule (notably an HLA A*02:01 molecule) and an irrelevant or cross-reactive peptide. The present disclosure encompasses an ABP that binds a peptide-MHC molecule complex comprising the peptide of SEQ ID NO: 1131 or a variant thereof as previously defined in association with an HLA A*02 molecule (notably an HLA A*02:01 molecule). Variants of the this peptide include peptides of 8 to 12 amino acids, wherein one or more of the isoleucine residues can be replaced by a leucine and / or wherein one or more of the leucine residues can be replaced by an isoleucine residue, and which bind an HLA A*02 molecule (notably an HLA A*02:01 molecule) with a KD of less than 100 nM as previously defined. Typically, the said ABP does not bind MHC-peptide complexes when the MHC molecule is not an HLA A* 02 molecule (notably an HLA A*02:01 molecule) (irrelevant of the associated peptide and including the peptide of SEQ ID NO: 1131). Typically, the said ABP does not bind MHC -peptide complexes comprising an HLA A* 02 molecule (notably an HLA A*02:01 molecule) and an irrelevant or cross-reactive peptide. An ABP directed against a molecular complex as described in the present disclosure can also be assessed for further functionalities, such as for example for its ability to drive immune cell, in particular immune effector cells (e.g. CTL or NK cells) activation and / or cell-mediated cytotoxicity. An ABP of the present disclosure can be included in various formats including cell surface antigen receptors (e.g. chimeric antigen receptor or CAR and T cell receptor, TCR) or multispecific antibodies such as immune cell engagers (ICEs), including T cell engagers (TCEs) and natural killer cell engagers (NKCEs) targeting at least an immune cell marker (e.g. CD3 for TCEs) and a target molecular complex comprising a P3 peptide and an HLA molecule, as per the present disclosure. Immune cell activation and / or target cell (i.e. cells expressing a target molecular complex) cytotoxicity can be evaluated using a variety of in vitro and in vivo assays well known in the art. These assays include, in a non-limitative manner, those described in Ravetch and Kinet, Annu. Rev. Immunol ., 1991, 9:457-492; U.S. Pat. Nos. 5,500,362, 5,821,337; Hellstrom et al., Proc. Nat Acad. Sci. USA, 1986, 83:7059-7063; Hellstrom etal., Proc. Natl Acad. Sci. USA, 1985, 82:1499-1502; Bruggemann etal., J. Exp. Med., 1987, 166: 1351-1361; Clynes etal., Proc. Nat’l Acad. Sci. USA, 1998, 95:652-656; WO 2006 / 029879; WO 2005 / 100402; Gazzano-Santoro et al., J. Immunol. Methods, 1996, 202: 163-171; Cragg et al., Blood, 2003, 101: 1045-1052; Cragg et al. Blood, 2004, 103:2738- 2743; and Petkova et al., Int’l. Immunol., 2006, 18: 1759-1769; each of which is incorporated by reference in its entirety.The target molecular complex can be in a soluble form, immobilized on a solid support or presented at a cell surface of a target cell or of an antigen presenting cell (APC).T cell activation can be for example measured by, assessing (1) proliferation, (2) up-regulation of activation markers (e.g., such as CD69, ILCD137 / 4-1BB, CD154 / CD40L, IL2AR / CD25, and / or PD-1 / CD279) and / or (3) production of effector cytokines (e.g. IFN-y, IL2, TNF-a) and / or expression of lysosomal associated proteins such as CD107a. As CD107a becomes accessible to antibody staining during effector cell degranulation, its expression is correlated with target cell lysis and is used as a marker or cell activation and cytotoxic degranulation. Typically, CD 107a as well as other activation makers (such as the one exemplified above) can be easily evidenced by immunofluorescence assay and flow cytometric analysis using typically monoclonal antibodies directed against the said markers as specific agents.Methods to measure cytokine production typically include enzyme-linked immunospot assays (ELISPOT), cytokine capture assays and intracellular cytokine staining (typically using specific fluorescence-labeled antibodies for cytokine staining after cell permeabilization and analysis by flow cytometry).In embodiments wherein the effector immune cells are expressing at their surface a antigen receptor targeting the target molecular complex (i.e. an ABP targeting the target molecular complex, for example in a CAR or in a TCR format), activation assays are typically performed by putting into contact the target molecular complex (whether immobilized on a solid support or expressed at the surface of a target cell or APC) and the effector cells. In other embodiments, activation assays can also be performed by putting effector cells into contact and the target molecular complex in the presence of an immune cell engager (e.g. TCE or NKCE), wherein the ICE targets at least the target molecular complex and an immune cell marker (such as typically CD3 for TCEs). Using experimental conditions as described in the examples (in particular exemplified target cell lines, E:T ratio, and when required ICE format and / or concentrations), an effector cell activation of at least, 15 %, notably at least 20 %; 30 %; 40 %; 50 %; 60 %; 70 %; 80 % is induced with an ABP of the present disclosure as compared to an activation assay performed in the presence of an irrelevant target molecular complex.An ABP of the present disclosure, directed against a target molecular complex as herein described, can drive cell-mediated (e.g. T cell or NK cell) cytotoxicity over a target cell expressing the said target molecular complex at its surface. In embodiments wherein the ABP is expressed at the cell surface of the immune effector cell (e.g. a T cell or an NK cell) as a target antigen receptor (e.g. a CAR or a TCR), the cytotoxic effect associated to said ABP can be assessed using various cytotoxic assays (such as e.g. a CTL assays) well-known in the field (see for reference Kiesgen, Stefan et al. “Comparative analysis of assays to measure CAR T-cell-mediated cytotoxicity. ” Nature protocols vol. 16,3 (2021): 1331-1342}. Such assays typically comprise the co-culture of (i) target cells expressing (i.e.: presenting) at their cell surface a target molecular complex and (ii) effector cells (e.g. purified T cells) expressing at their cell surface an antigen receptor (e.g. a CAR or a TCR, but see herein after for more detailed description or antigen receptor formats) comprising an ABP as herein described and directed against the said target molecular complex. In other embodiments, the ABP can be in the form of a soluble ICE (e.g., a TCE or an NKCE, but see also description hereinafter for more details on ICE formats). In such embodiments, cytotoxic assays can be performed by co-culturing effector cells (e.g. T cells or NK cells) and targets cells expressing at their cell surface a target molecular complex, in the presence of the ICE targeting the said target molecular complex. Typically, at least 30 %, notably at least 40 %; 50 %; 60 %; 70 %; 80 % lysis of target cells is achieved. Typically, when non-matching target cells (i.e. cells that do not express the target molecular complex targeted by the TCE or the antigen receptor), no more than a residual cytotoxicity should be observed (e.g. typically less than 20 %, notably less than 10 %; less than 5 %; or less than 2 % lysis of the non-matching targets cells).Well-suited CTL assays according to the present invention are exemplified in the enclosed results for ABPs of the present disclosure expressed as CAR T cells or TCEs (in a BiTE format). As a matter of example target cell lysis by effector cells (i.e. cytotoxic T lymphocytes or NK cells) can be followed by flow cytometric assays that use fluorescent dyes (such as carboxyfluorescein succinimidyl ester (CFSE), PKH-2, and PKH-26) which are lipophilic and integrate into the cell membrane, or bioluminscence imaging (BLI) assays. BLI is based on light detection from a variety of light-emitting enzymes such as luciferases using highly sensitive cameras or luminometers. Luciferase is used most frequently for BLI imaging. Since BLI is ATP-dependent, a dying cell will stop emitting BLI once its remaining intracellular ATP has been used up. Thus, by using luciferase-transduced (expressing) target cell lines, NK and CTL cellular cytotoxicity can be detected as a decrease in BLI.For example, functional assessment of an ABP of the present disclosure, formatted as an immune cell engager (ICE) format such as a TCE can be achieved as follow, illustrated for ABPs targeting an MHC -peptide (P12) molecular complex. Any cell line validated for the expression (includingendogenous or ectopic expression obtained by transduction) of both HLA- A* 03 and / or HLA-A*011 molecules and a P12 peptide as herein defined (wherein the peptide can be endogenously or ectopically expressed or loaded by peptide pulsing) can be used. As a matter of example, the expression of nucleic acid transcripts encoding the P12 peptide has been validated qPCR in cell lines, including 7 LUAD / LUSC cell lines (such as H1650, A549, SK-MES-1), 13 COAD / READ cell lines (including HT-29, NCI-H508, SW837), EFO-21 ovarian cell line, and 2 pancreatic cell lines (BxPC3 and CFPAC-1) and in 16 cell lines by dPCR, including 4 LUAD / LUSC cell lines (H1650, A549, SK-MES-1, HCC827), 4 COAD / READ cell lines (HT-29, NCI-H508, SW837, SNU-C1), and CFPAC-1 pancreatic cell line. Cell lines not expressing the relevant HLA allele can be further transduced with a recombinant construct coding for the said HLA molecule. As previously explained, cell lines that do not express either the peptide or the HLA allele of interest (either naturally or either by genetic engineering, e.g by KO) can be used as negative control. As a further matter of illustration, LN229 cells naturally expressing Pl 2 and HLA-A*03 or transduced with HLA-A*011, can be used as target cells. Typically, a 5: 1 effectortarget ratio can be used and in the presence of a matching TCE (i.e. specific for a P12 peptide presented on HLA-A*03 or an HLA-A*011 molecule) at a concentration ranging from 0.05 to 5 nM. Tandem scFv (i.e.BiTE®) format, including a CD3 scFv, are well-suited (see for example the CD3 scFv of SEQ ID NO: 1166 but see also linker sequences of SEQ ID NO: 1141-1159 that are broadly used in binder’s constructs). The target cells can be transduced with luciferase for cytotoxicity assessment. Typically, after 48h of incubation, the plates can be measured for luciferase activity and specific lysis is calculated by the decrease in luciferase signal.Functional assessment of an ABP of the present disclosure reformatted as an antigen receptor, for its ability to drive immune cell-mediated cytotoxicity (CTL or NK-cell mediated cytotoxicity) can be performed as exemplified in the results and summarized herein after. Briefly, effector cells (e.g. T cells expressing a CAR directed against a P12 MHC -peptide molecular complex as herein described) can be co-cultured with target cells expressing the said target molecular complex (for P12 see above and in Figure 6). In some embodiments, target cells can be modified to express a reporter gene (e.g. BFP, GFP, YFP, luciferase, etc.) and specific lysis can be followed by fluorescence and / or bioluminescence. The examples herein notably provide illustration of cytotoxic assays wherein the ABP is reformatted as a chimeric antigen receptor (CAR) expressed at the surface of a T cell. As mentioned above, any cell line validated for the expression (including endogenous or ectopic expression obtained by transduction) of both HLA- A* 03 and / or HLA-A*011 molecules and a P12 peptide as herein defined (wherein the peptide can be endogenously expressed, ectopically expressed or loaded by peptide pulsing) can be used. As a matter of example, LN229 cells naturally expressing a P12 peptide and HLA-A*03 or transduced with HLA-A*011can be used as target cells. Typically, an E:T ratio of 1:1 can be used, and bioluminescence can be measured after 24h of co-culture.It is of course intended that functional assessment of an ABP is not limited to the above-described assays nor limited to the specific example implementation provided, as functional assays are broadly used in the field by the skilled persons.Methods for identifying, screening or producing an antigen binding protein (ABP)The present disclosure also encompasses a method of identifying, screening and / or producing an antigen binding protein as herein disclosed.ABPs that bind a molecular complex according to the present disclosure can be screened using any method known in the art, e.g., phage display, immunization of an animal or a subject, or isolation of an ABP expressing cell (typically a T cell expressing a TCR) from a subject’s sample and optionally subsequent sequencing of the ABP and / or genes encoding thereof.The present disclosure further provides a method of using a tumor antigenic peptide as herein described or a molecular complex comprising thereof for identifying an antigen-binding protein targeting the said peptide or molecular complex, said method comprising steps of :(a) immunizing an animal (typically a mammal, e.g., a mouse, rabbit or a llama) with the tumor antigenic peptide, optionally wherein the peptide can be or not bound (covalently or not) to a matched MHC molecule to form a molecular complex (optionally in combination with an adjuvant) as defined in the present application, optionally wherein the animal is a transgenic animal expressing the matched human HLA allele.(b) isolating the antigen binding protein from the subject, wherein isolating the antigen binding protein can include screening the serum of the subject to identify the antigen binding protein, and (c) detecting or isolating one or more antigen binding proteins that bind to the molecular complex, optionally with a KD of about 10'6M or less (lower numbers indicating increasing affinity).Transgenic animals according to the present disclosure typically include HLA transgenic animals. Typically, the animal can be further humanized by knock-in of human TCR variable chained into the genetic loci encoding the endogenous TCR chains. TCR produced by such animals thereof possess fully human TCR variable sequences.In some embodiments, step (b) comprises contacting primary B cells or hybridomas generated from the animal’s B cells with the molecular complex as defined in step a).The present disclosure also provides a method of using a tumor antigenic peptide for identifying an antigen-binding protein, comprising the step of (a) contacting a library of different antigen-binding domains, or cells displaying different antigen-binding domains, with a molecular complex of thepresent disclosure, and (b) detecting or isolating one or more antigen binding proteins that bind to the molecular complex, optionally with a KD of about 10'6M or less.Target molecular complexes as per the present disclosure have been described previously herein and can be typically immobilized on a solid surface (such as a bead, including a magnetic bead, a well, including an ELISA well, a membrane, a tube, a column, a plate, sepharose, a cell, or a chip such as an SPR or BLI sensor chip) or expressed at a cell surface.In some aspects, the binding steps (a) and / or (b) are performed more than once, optionally at least three times, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times.Libraries that are usable according to the method of the present disclosure encompasses naive, immune libraries as well as engineered libraries.In some embodiments, the library is a human library. In some embodiments of the system, the library is a humanized library.In some embodiments, the library is a phage display library. Typically, in a phage library each phage displays a unique binding protein. Therefore, it is possible to select different phage particles by assessing whether they bind the target and thereby isolate the binding proteins that have the desired specificity. The bound phages are then eluted and amplified in bacteria (see for example reference: Chames P, Hufton SE, Coulie PG, Uchanska-Ziegler B, Hoogenboom HR. Direct selection of a human antibody fragment directed against the tumor T-cell epitope HLA-A1-MAGE-A1 from a nonimmunized phage-Fab library. Proc Natl Acad Sci U S A (2000) 97:7969- 74). The phage display library can be developed so that it is substantially free of antigen binding proteins that non-specifically bind the target molecular complex. Each phage particle comprises the nucleic acid sequence that codes the particular binding protein that is expressed on its cell surface. In some embodiments, the binding protein is a unique antibody (a scFv or a Fab fragment) expressed typically as a fusion protein on the phage surface. In some embodiments, the binding protein is a TCR or is derived from a TCR. Typically, the binding protein is a single chain TCR wherein TCR a and 0 variable domains (Va and V0) are linked via a flexible linker, akin to a single-chain variable fragment (scFv). Phage display, with its large potential library size ('IO12- IO13), stable genotypephenotype link and cost-effectiveness, is a very relevant method of generating clinically translatable soluble TCRs. Moreover, heterodimeric VaCa / Vpcp TCRs can be robustly expressed on phage particles. As mentioned by Robinson, Ross A et al. (FEBS Journal 2021) : Phage display using a CDR walking library design, targeting up to six sequential amino acid positions at a time with degenerate NNK codons and combining the resulting mutations, has been successful in dramatically increasing the affinity of TCRs into the low picomolar-high femtomolar range (Robinson, Ross Aet al. “Engineering soluble T-cell receptors for therapy. ” The FEBS journal vol. 288,21 (2021): 6159-6173').When a phage display library is used, the above-mentioned method typically involves biopanning steps, wherein the library is exposed to the target molecular complex. Steps of biopanning can include one or more of the following steps:a. an incubation step, wherein the library is incubated with the target molecular complex; b. one or more washing steps, to remove weak or non-specific binders;c. one or more elution steps, wherein binders with increased specificity for the target molecular complex are selected (i.e. eluted);d. an amplification step wherein the recovered phages or yeasts are reinfected into a eukaryotic or prokaryotic cell (typically E. coli) to amplify the selected clone (i.e. expressing the selected binders);wherein one or more of the above steps can be repeated 2 to 5 times to enrich for high affinity binders.In step b. and / or c. above, clones that bind the target molecular complex can be selected using a phage ELISA and affinity selection.Binders with increased specificity for the target molecular complex can typically be selected using by using a combination of target molecular complexes and or non-target molecular complexes comprising a competitive (e.g.: similar) peptide (also named cross-reactive or similar peptide) (see for example, cross reactive peptides of SEQ ID Nos: 1264-1270 in Table 12) and / or a different MHC molecule as the target molecular complex, and / or by performing the selection step in low pH conditions.In some embodiments, the library is a yeast display library. Typically, the antigen binding protein (e.g. an scFv or a fab) is anchored in the yeast cell membrane. The yeast display library can be developed so that it is substantially free of antigen binding proteins that non- specifically bind the target molecular complex. In some embodiments, the binding protein is a TCR or is derived from a TCR. Typically, the binding protein is a single chain TCR wherein TCR a and 0 variable domains (Va and V0) are linked via a flexible linker, or an a / 0 heterodimer (potentially stabilized by an added disulfide bond in the constant region). Similarly, each host expresses a single binding molecule or heterodimer. Selection of clones that specifically bind a target molecular complex can be performed using FACS-based magnetic sorting. Yeast display methods have notably shown particular promise with single-chain formats that have been used to generate TCRs with low nanomolar affinities and have the key advantage that the stable display on the yeast surface tendsto correlate with the stability of the soluble TCR (see Robinson, Ross A et al. “Engineering soluble T-cell receptors for therapy. ” The FEB S journal vol. 288,21 (2021): 6159-6173).After identification of high affinity clones, individual binder’s clones can be further tested for binding specificity and affinity using binding assays (e.g. ELISA, SPR, BLI, flow cytometry) and / or functional validation assays (e.g. T cell activation assays, CTL assays) as previously defined (but see also below for further bibliographic references).Accordingly, provided herein are systems for identifying ABP that selectively binds a molecular complex described herein. In some embodiments, the system comprises (a) a molecular complex as herein defined; and (b) a library comprising a plurality of distinct antigen binding proteins. In some embodiments, the library is a phage display library or a yeast display library.In some embodiments of the system, the molecular complex is attached to a solid support as previously described. The solid support can comprise, e.g., ahead, well, membrane, tube, column, plate, sepharose, magnetic bead, cell, or chip. In some embodiments, the molecular complex comprises a first member of an affinity binding pair and the solid support comprises a second member of the affinity binding pair. In some embodiments, the first member is streptavidin and the second member is biotin. In some embodiments, the antigen attached to solid support is a multimer (e.g., a tetramer).In some embodiments, the system further comprises a non-target molecular complex, typically wherein the HLA-restricted peptide is located in the peptide binding groove of a heterodimer portion of the HLA I molecule, and wherein the non-target molecular complex comprises a different restricted peptide, a different HLA Class I molecule, or a different restricted peptide and a different HLA Class I molecule. In some embodiments, the non-target molecular complex comprises a different restricted peptide but the same HLA Class molecule as the target molecular complex. In some embodiments, the HLA restricted peptide of a non-target molecular complex is a competitive or a cross-reactive peptide, wherein the HLA molecule is typically the same as the HLA molecule of the target molecular complex. In some embodiments, the HLA restricted peptide of a non-target molecular complex is an irrelevant peptide.In some embodiments, the system comprises a reaction mixture, the reaction mixture comprising the molecular complex and a plurality of phages or yeasts from respectively the phage- and the yeast display library.The present disclosure also provides methods of using a molecular complex as herein described for purifying an antigen-binding protein, comprising (a) contacting cell medium or cell extracts with the molecular complex, and (b) isolating one or more antigen binding proteins that bind to the tumor associated peptide, optionally with a KDof about 10'6M or less.The present disclosure further encompasses methods of using a molecular complex as previously defined in quality control, optionally during manufacture of an antigen-binding protein, comprising (a) contacting a batch of antigen-binding protein with the molecular complex (optionally bound on a support or displayed at a cell surface), and (b) detecting binding, optionally with a KDof about 10'6M or less.One method of identifying an antigen binding protein includes providing at least a target molecular complex; and binding the at least one target molecular complex with an antigen binding protein, thereby identifying the antigen binding protein.In any of the above methods, the antigen binding protein (ABP) can be tested for binding specificity and affinity using binding assays (e.g. ELISA, SPR, BLI, flow cytometry) and / or functional validation assays (e.g. T cell activation assays, CTL assays) as previously defined, wherein the ABP binds the target molecular complex with a KDof about 10'6M, about 10'7M or less, 10'8M or less or about 10'9M or less or about 10'10M or less or about 10-11M or less.The method as defined above can also include a step contacting the antigen binding protein with one or more non-target molecular complex(es), notably one or more non target molecular complex(es) comprising the same or different cross-reactive peptides. Such step can be used in a method, of screening an ABP that specifically binds a molecular complex as herein disclosed with a high selectivity, in other words to assess cross-reactive binding (see for example Wittman, Vaughan P et al. “Antibody targeting to a class I MHC-peptide epitope promotes tumor cell death. ” Journal of immunology (Baltimore, Md. : 1950) vol. 177,6 (2006): 4187-95).In some embodiments, of the above-described methods and systems to be used in the said methods, a cross-reactive peptide (also named competition or counter selection peptide) of a given target MHC peptide according to one or more of the following criteria:Peptides of 8 to 15, notably of 8 to 12, notably of 9 to 12 amino acid residues that specifically binds the same HLA molecule of the target MHC peptide with a binding affinity (Kd) of less 10'6M, notably 10'7M or less, notably 10'9M or less, notably IO'10M or less as previously defined, or with an IC50 of 50.1 O'9M or less wherein :the peptide has a sequence having at least 50% similarity with the sequence of the target peptide, notably between 50 and 99% similarity, between 60 % and 99% similarity, between 70 % and 99% similarity or between 80 % and 99% similarity, or between 70 % and 95% similarity. the peptide is derived from a canonical protein or polypeptide, optionally wherein the protein or polypeptide is expressed in healthy tissues;the peptide is expressed at the cell surface of normal cells (typically cells from healthy tissues) in association with the same HLA molecule as the target molecular complex.For example, when the target peptide is the MIHI peptide of SEQ ID NO:252 , counter-selection peptides or cross reactive peptides can be chosen among peptides of 8 to 12, notably of 9 to 12 amino acid residues that that specifically bind an HLA* A3 and / or an HLA *A11 molecule with an IC50 of 50 10'9M or less and that have an amino acid sequence having at least 50 %, notably at least 60% similarity with the MIHI peptide or a variant thereof as herein described.Cross reactive peptides are typically chosen from peptides of the human peptidome, notably peptides for which evidence (notably immunopeptidomic evidence) for presentation at a cell surface (typically at a normal non-disease cell surface) in association with an HLA A3 or All molecule have been found. In some embodiments, cross-reactive peptides are also found in the healthy peptidome. In some embodiments, cross reactive (similar) peptides are selected among peptides of Table 12 (SEQ ID NO: 1200-1214).In some embodiments, the identified antigen binding protein is humanized.Another method of the present application comprises the identification of an antigen binding protein (ABP) directed against a target molecular complex among a plurality of cells expressing a plurality of ABP. Said method includes the steps of contacting the plurality of cells with a target molecular complex as herein described (e.g., a tetramer), and identifying the antigen binding protein via binding between the target molecular complex and the cell expressing at its surface an ABP that specifically binds to the said target molecular complex.Another method of identifying an antigen binding protein directed against a target molecular complex can include obtaining a cell expressing the antigen binding protein (ABP), isolating the ABP and sequencing it.In some aspects, the antigen binding protein is a TCR.In some embodiments, isolation is carried out by enrichment for a particular cell population by positive selection, or depletion of a particular cell population, by negative selection. In some embodiments, positive or negative selection is accomplished by incubating cells with one or more antibodies or other binding agent that specifically bind to one or more surface markers expressed or expressed (marker+) at a relatively higher level on the positively or negatively selected cells, respectively. For example, a population of cells known or suspected to contain T cells can be positively sorted based on binding to a target molecular complex. FACS isolation can also include removing cells that bind to at least one non-target molecular complex. For example, cells can be positively sorted based on binding to a target molecular complex and negatively sorted based on binding to a non-target molecular complex comprising an irrelevant peptide and / or an irrelevant HLA molecule.Isolation of cells expressing an ABP-containing protein (e.g. FACS-based isolation of T cells), can include isolation of subject-derived cells. Subject-derived cells can be isolated from a variety of biological samples including, but not limited to, body fluids, such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine and sweat, tissue and organ samples. The biological sample can be a sample obtained directly from a biological source or a sample that is processed. The sample from which the subject-derived cells are derived or isolated can be blood or a blood-derived sample or can be derived from an apheresis or leukapheresis product. Exemplary samples include whole blood, peripheral blood mononuclear cells (PBMCs), leukocytes, bone marrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph node, gut associated lymphoid tissue, mucosa associated lymphoid tissue, spleen, other lymphoid tissues, liver, lung, stomach, intestine, colon, kidney, pancreas, breast, bone, prostate, cervix, testes, ovaries, tonsil, or other organ, and / or cells derived therefrom. Exemplary cells and cell populations expressing an ABP-containing protein, in particular a TCE include, but are not limited to, an activated T cell, a tumor infiltrating lymphocyte (TIL), a PBMC, a cultured (e.g. expanded) T cell, a naive T (TN) cell, an effector T cell (TEFF), a memory T cell, a stem cell memory T cell (TSCM), a central memory T cell (TCM), an effector memory T cell (TEM), a terminally differentiated effector memory T cell, an immature T cell, a mature T cell, a helper T cell, a cytotoxic T cell, a mucosa-associated invariant T (MAIT) cell, a regulatory T cell (Treg), a THl cell, a TH2 cell, a TH3 cell, a TH17 cell, a TH9 cell, a TH22 cell, a follicular helper T cell, an natural killer T cell (NKT), an alpha-beta T cell, and a gamma-delta T cell.The present disclosure therefore encompasses a method for screening a TCR that specifically binds an MHC peptide according to the present disclosure in association with a matched HLA molecule (i.e. a molecular complex according to the present disclosure). The method typically comprises a step of isolating a T cell from a sample obtained from a subject or a cell line that expresses the target peptide and its matched HLA molecule. Typically, a molecular complex comprising the said target peptide and HLA molecule can be used to isolate T cells expressing a TCR that specifically binds the said molecular complex. Typically, a labeled molecular complex (e.g. a tetramer labeled with a fluorophore and comprising 4 biotinylated peptide-MHC monomers with fluorophore-conjugated streptavidin) can be used to bind and stain T cells. Stained T cells can then be analysed using FACS or magnetic beads and antigen (molecular complex)-specific T cells can be isolated or sorted based on fluorescence. In some embodiments, the sample obtained from the subject include non limitatively: whole blood, isolated peripheral blood mononuclear cells (PBMCs), leukocytes, bone marrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph node, gut associated lymphoid tissue, mucosa associated lymphoid tissue, spleen, or other lymphoid tissues.As previously described, binding specificity of complex-specific T cells can also be assessed in competitive binding assays using one or more non-target molecular complex(es) comprising a cross-reactive peptide as previously described.Another method of identifying an antigen binding protein targeting a molecular complex according to the present disclosure, includes:obtaining one or more cells expressing an antigen binding protein (typically a T cell as above defined expressing a TCR)putting the said one or more cells into contact with at least one at least one target molecular complex or target peptide loaded APC as above described; andfunctionally identifying one or more target antigen binding protein via selection of one or more cells that are activated by interaction with said at least one at least one molecular target or target peptide loaded APC.The T cell can be obtained from a subject’s sample as previously defined. In some embodiments, the donor subject is known to have zero or reduced immune tolerance to a tissue of origin of the peptide from the target molecular complex. Without wishing to be bound to a certain theory, a subject, e.g., a human, can normally develop immune tolerance to proteins or peptides that are encoded by almost all normal genes (e.g., wildtype genes) of the subject in a healthy somatic tissue. However, in some cases, when a tissue of the same species is heterologous to the subject and / or expressed at a low or undetectable level by the subject, the subject can have zero or low immune tolerance to proteins or peptides that are normally expressed in such tissue.Once antigen-specific T cells are isolated, their TCRa and TCR0 chain genes can be amplified and sequenced. Sequencing of cells expressing an ABP-containing protein can carried out by techniques known to those skilled in the art, such as the Chromium Single Cell Immune Profiling system (lOx Genomics), Smart Seq or any other single cell platform.In some embodiments, the TCR genes encoding the TCR can be cloned, for example into an expression vector, typically a mammalian expression vector (including e.g. plasmid vectors or viral vectors) for expression in a recipient cell. Typical recipient cells include cell lines (such as e.g cell lines to be used in functional assay such as HEK cells or Jurkat cells, such as Jurkat reporter cells) or primary T cells.The T cell can also be used to create a hybridoma. The T cell can also be used for cloning one or more of its CDRs. The T cell can also be immortalized, for example, by using EBV transformation. Sequences encoding an antigen binding protein can be cloned from immortalized T cells or can be cloned directly from T cells isolated from an immunized subject. A library that comprises theantigen binding protein of the T cell can also be created, optionally wherein the library is phage display or yeast display.Assays for mapping the epitopes to which an ABP provided herein bind are described, for example, in Morris “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66, 1996, Humana Press, Totowa, N. J., incorporated by reference in its entirety. In some embodiments, the epitope is determined by peptide competition. In some embodiments, the epitope is determined by mass spectrometry. In some embodiments, the epitope is determined by mutagenesis (typically using different point mutation such as the alanine scanning assay). In some embodiments, the epitope is determined by crystallography.Antibody-based ABPsThe present disclosure encompasses an antibody directed against a peptide MHC molecular complex comprising a MAP as herein described (e.g. a MAP encoded by a transcript of the gene NIHCOLE such as a transcript of Tables 6-7, a fragment or a variant thereof, or a peptide comprising a portion of any one of the sequences of Table 8 and variants thereof, or a MAPs as disclosed in Tables 4-5 or a variant thereof) and an HLA molecule. In some embodiments, the present disclosure encompasses an antibody (ABP) directed against a target molecular complex comprising (i) a peptide any one of SEQ ID NO: 1034 and 1064 or a variant thereof in association with an HLA A*03:01 or an HLA A* 11:01 molecule, or (ii). a peptide any one of SEQ ID NOs: 1089, 1101 and 1131 or a variant thereof in association with an HLA A*02:01 molecule. As used herein, the term "antibody” encompasses antigen binding molecules (e.g.: immunoglobulins and immunoglobulin-like molecules) such as those produced during an immune response in any vertebrates (e.g., mammals, such as humans, goats, rabbits, camelids, chicken, rats and mice, as well as non-mammalian species, such as sharks). Antibodies can be produced by various techniques including immunization of an individual with an antigen, phage display, recombinant technologies and / or chemical synthesis.Unless otherwise stated, the term "antibody" encompasses more specifically functional immunoglobulins, notably intact or full-length immunoglobulins of any class or sub-class, in particular: IgGs and sub-classes thereof (i.e. IgGl, IgG2, IgG3, IgG4), IgMs, IgEs, IgAs, and IgDs. Preferably an antibody of the present disclosure is an IgG or is derived from an IgG molecule or is a variant thereof. In preferred embodiments, the present application encompasses antibody constructs that comprise at least one IgG or a binding fragment thereof. Antibodies of the present application include both polyclonal and monoclonal antibodies. In some embodiments, the antigen binding protein can be present in a library comprising a plurality of distinct antigen binding proteins.The present application further encompasses functional fragments (i.e. antigen-binding fragments) of immunoglobulins (notably of IgGs) and any combinations thereof.The term “antibody” broadly encompasses genetically engineered and / or otherwise variants and modified forms of immunoglobulins, such as recombinant antibodies, chimeric or fusion antibodies, humanized antibodies, fully human antibodies, intrabodies, peptibodies, heteroconjugate antibodies, as well as multi-specific antibody scaffolds or constructs.In some embodiments, the antibody, or antibody construct of the present disclosure comprises a chimeric antigen binding domain or chimeric antibody (e.g.: a chimeric mouse / human antibody). The term "chimeric antibody" typically refers to a monoclonal antibody or an antigen binding fragment thereof which comprises a VH domain and a VL domain of an antibody derived from a non-human animal, a CH domain and a CL domain of a human antibody. As the non-human animal, any animal such as mouse, rat, hamster, rabbit or the like can be used. In particular, said mouse / human chimeric antibody may comprise the VH and the VL domains of the present reference antibody.In some embodiments, the antibody, or antibody construct of the present disclosure comprises at least one humanized antigen binding domain. As used herein the term "humanized antibody" or humanized binding domain, refers to antibodies or binding fragments thereof in which the framework regions (FRs) have been modified to comprise the FRs from a donor immunoglobulin of different species (for example human species) as compared to that of the parent immunoglobulin (for example murine CDRs).In some embodiments, the antibody or antibody construct comprises at least one binding domain that is made of fully human amino acid sequence(s). Typically, fully human antigen binding domains can be selected either in vivo by the use of genetically modified animals or by antibody engineering processes combined with screening (including bacteriophage or yeast display techniques).In some embodiments, the antibody of the present disclosure is selected from the group consisting of immunoglobulins (in particular IgGs), single-domain antibodies including VH and VL single antibodies, sdFv, VHH antibodies or nanobodies, (see for review on VHH and variants thereof: Jin, B. K., Odongo, S., Radwanska, M., & Magez, S. (2023). Nanobodies: A Review of Generation, Diagnostics and Therapeutics. International journal of molecular sciences, 24(6), 5994), antigen binding fragments thereof or any fusion proteins comprising thereof. In preferred embodiments, the antibody comprises at least one binding domains that include one, two, three, four, five, or six CDRs of an immunoglobulin (notably an IgG), e.g. of a VH and / or VL region. In some embodiments, the antibody comprises at least a binding domain comprising a VL and a VH domain from animmunoglobulin, notably from an IgG (that can be from mamalian origin, humanized or fully human). The light chain may be a lambda or a kappa light chain; preferably a Kappa light chain. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHI domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain, or any fusion proteins comprising such antigen-binding fragments. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a peptide linker (PL) that enables them to be made as a single chain protein in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see . ,., Bird etal., 1988 Science 242:423-426; and Huston etal., 1988 Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigenbinding fragment" of an antibody.In some embodiments, peptide linkers (PL) can be used for interconnexion of various immunoglobulin domains or fragments (e.g. light chain variable domain, light chain constant domain, heavy chain variable domain, heavy chain constant domain, the Fc region such as the CH2 and CH3 regions, etc) or for connection to other peptidic sequences. As a matter of examples, PLs can be used to build antibody constructs notably multispecific antibody constructs by connecting antibody fragments and / or full antibody together. Well-known PLs include notably those used in scFVs which are connecting amino acid sequences of VH and VL domains (such linkers join the carboxyl terminus (C-terminus) of one variable region domain to the amino terminus (N-terminus) of the another variable domain without compromising the fidelity of the VH-VL paring and antigen-binding sites), as well as those used in tandem scFvs (e.g.: BiTEs), which are also further exemplified below. Peptide linkers can vary from 2 to 40 amino acids in length, notably including 2; 3; 4; 5; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34 or 35 or more amino acids; notably of 5 to 25 or about 10 to about 25 amino acids or 10 to 40, notably 10 to 35 amino acids. Natural and synthetic linkers can be used for fusion proteins. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility, but linkers comprising randomly selected amino acids selected from the group consisting of valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, glycine, and proline may also be suitable. A well-suited linker according to the present disclosure contains glycine and serine residues and is for example of the format (G4S)p, (G3S)p or (SG)p, with p is an integer comprised between 1 and 8, notably between 1 and 4, notably p is 2; 3 or 4. Thelinker may also be selected from the group consisting of the amino acid sequences: SEQ ID 1 Mill 59, including the Withlow linker of SEQ ID NO: 1156 (GSTSGSGKPGSGEGSTKG) (see Raag, R, and M Whitlow. “Single-chain Fvs. ” FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 9,1 (1995): 73-80, the content of which is included herein by reference). In some embodiments, short PLs such as the GGG sequence can be used to connect scFvs.Other well described PLs include hinge regions, notably hinge region or natural IgG or mutated hinge region thereof, or domain that is a short an amino acid sequence connecting the Fab region (through the CHI domain of the heavy chain) to the CH2 domain of the Fc region in IgG, IgA, and IgD antibody isotypes (see for example SEQ ID NO: 182-189). In preferred embodiments, antibodies of the present invention that comprise an Fc region include a hinge from an IgGl, IgG2, IgG3, or IgG4 subclass that can be native or not. In some embodiments the hinge can be an engineered (i.e. mutated) amino acid sequence derived from an IgGl, IgG2, IgG3 or an IgG4 isotype. Preferably also, the hinge sequence is of human origin. Typical hinge sequences comprise between 10 and 20 amino acids, notably between 12 and 15 amino acids. In some embodiments, the hinge sequence is of any one of SEQ ID NO: 1157-1159.Antibodies of the present application may or may not comprise an Fc domain. Indeed, while the existence of the Fc domain enables antibodies to exhibit prolonged half-time, binding of the Fc domain on its receptor on multiple immune cells can induce nonspecific immune activation such as ADCC, leading to unwanted toxicity. Fc domain typically includes the CH2 and CH3 domains of an immunoglobulin, notably the CH2 and CH3 domains of an IgG. In some embodiments, the Fc domain also includes a hinge region. Antibodies comprising an Fc domain typically include IgG-based antibodies and immunoglobulin binding fragments as above described that can be fused with an Fc domain (Fc fusions), wherein the binding fragment and the Fc domain can be from the same or different immunoglobulin, notably IgG isotypes. IgG-based antibodies also include fusion molecules wherein the Fab, the hinge and the Fc region are native, or from different immunoglobulins, notably different IgG isotypes. In some embodiments, the Fc domain comprises a single chain fragment wherein the 2 two identical protein fragments, derived from the second and third constant domains of an antibody (i.e. CH2 and CH3 domains) are connected by a peptide linked (PL) as described above.In some embodiments, an antibody (including multispecific antibody construct) of the present application comprises an Fc silent domain. In some embodiments, the antibody of the present application comprises an Fc domain of IgGl, IgG2, IgG3 or IgG4 isotype. More particularly, Fc domains from IgGl or IgG4 isotypes may be favored when ADCC activity and / or C2q binding is not required and / or should be limited. In some embodiments, the antibody of the present disclosurecomprises a Fc portion that does not induce antibody dependent cellular cytotoxicity (ADCC) and / or comprises an “Fc silent” domain. In some embodiments, the antibody of the present disclosure comprises a Fc portion that does not induce antibody dependent cellular cytotoxicity (ADCC). As used herein, the term “silent” antibody refers to an antibody that exhibits no or low ADCC activity as measured in an in vitro ADCC activity assay, in which NK cells are co-incubated with target cells in the presence of the tested antibodies during several hours before measuring NK cell activation and target cells lysis. In one embodiment, the term “no or low ADCC activity” means that the silent antibody exhibits an ADCC activity that is below 50%, for example below 10% of the ADCC activity that is observed with the corresponding wild type (non-silent) antibody for example with a wild type human IgGl antibody. Typically, no detectable ADCC activity is observed in an in vitro ADCC activity assay with a silent antibody as compared to a control Fab antibody.Many antibodies with silent Fc domains have been developed by introducing point mutations the Fc constant portion of IgG that abrogate the binding of Fc receptors to Fc domains to reduce or avoid unnecessary effector functions while retaining the ability to extend the half-time, some of which are described in the following references, the content of which is included herein by reference: Ishiguro T, Sana Y, Komatsu S, Kamata-Sakurai M, Kaneko A, Kinoshita Y, et al., Sci Transl Med. 2017;9:eaal4291 ; Klupsch K, Baeriswyl V. Scholz R, Dannenberg J, Santimaria R, SennD, etal. Abstract 1787; Cancer Res. 2018; 78: 1787 ; Liu L, Lam CK, Long V, WidjajaL, Yang Y, Li H, et al., Clin Cancer Res. 2017,23: 1506-18 ; Mayes P, Tacken P, Wang S, Loo PV, Condamine T, Maaden HVD, et al. Abstract 539; Cancer Res. 2019; 79:539 ; Seckinger A, Delgado JA, Moser S. Moreno L, NeuberB, Grab A, et al., Cancer Cell. 2017;31:396-410 ; Schlothauer T, Herter S, Koller CF, Grau-Richards S, Steinhart V, Spick C, et al., Protein Eng Des Sei.2016;29:457-66 ; Chornoguz O, Leettola CN, Leander K, Brosnan K, Emmell E, Chiu ML, et al., Monoclon Antib Immunodiagn Immunother. 2019;38:242-54 ; Engelberts PJ, Hiemstra IH, de JongB, Schuurhuis DH, Meesters J, Beltran Hernandez I, etal., Ebiomedicine. 2020; 52: 102625. Silenced effector functions can be obtained by mutation in the Fc constant portion of the antibodies and have been described in the art: Strohl 2009 (LALA & N297A); Baudino 2008, D265A (Baudino et al., J.Immunol. 181 (2008): 6664-69, Strohl, CO Biotechnology 20 (2009): 685-91). Examples of silent IgGl antibodies comprise mutations reducing ADCC at positions 234, 235, 239, 265, 297, 329 and / or 331 in the IgGl Fc amino acid sequence (EU numbering). Another silent IgGl antibody comprises the N297A mutation, which results in aglycosylated or non-glycosylated antibodies. For example, an IgGl Fc silent fragment comprising specific mutation or combination of mutations can be utilized including but not limited to: D265A / P329A; L234F / L235Q / K322Q (FQQ); L234A / L235A (LALA); L234A / L235A / K322A (LALAKA); N297Q (aglycosyl); N297A;L234F / L235E / P331S (FES); L234A / G237A; L234A / L235E; L234A / L235A / G237A / P238S / H268A / A330S / P331S; L234A / L235A / P329G (LALAPG); G236R / L328R; or specific combination of positional substitutions of any of the following residues: L234A, L235A, G236R, G237A, P238S, H268A, L328R, A330S, P331S (EU numbering).In some embodiments, the antibody of the present disclosure comprises an Fc domain that is not capable of substantially binding to a FcgRIIIA (CD 16) polypeptide. In some embodiments, the antibody of the present disclosure lacks all or a portion of the Fc domain (e.g. lacks a CH2 and / or CH3 domain) or comprises an Fc domain of IgG2 or IgG4 isotype. In some embodiments, one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered C2q binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos.6,194,551. Any of the molecules described herein can be modified to contain additional non-proteinaceous moieties that are known in the art and readily available, e.g., by PEGylation, hyperglycosylation, and the like. Modifications that can enhance serum half-life or stability against proteolytic degradation are of interest.The antibodies of the invention may be glycosylated or not and may show a variety of glycosylation profiles. In some embodiments, antibodies are unglycosylated on the variable region of the heavy chains but are glycosylated on the Fc region.The present disclosure more specifically provides antibodies, in particular IgGs, (including binding domain fragments thereof), defined as binders 1-5, that bind a molecular complex as described herein, in particular that :(i) bind a molecular complex comprising a peptide of SEQ ID NO:1034 and an HLA A*03:01 molecule as previously defined, and(ii) that are structurally characterized by their variable heavy chain (VH) and variable light chain (VL) amino acid sequences as described in the Table 4 and / or their complementary determining sequences (CDRs) as defined in Table 5 below.Table 4: Variable heavy and light chain amino acid sequences of MNO P3 bindersIn some embodiments, the ABP comprises an scFv of any one of SEQ ID NO: 1169, 1185, 1201 or 1217.In Table 5 below, the CDR regions of some antibodies of the present disclosure are delineated using the IMGT system (LefrancMP et al. IMGT, the international ImMunoGeneTics database. Nucleic Acids Research (199) 27.1: 209- -212) and the Chothia numbering system (Chothia C, LeskAM.1987, J Mol Biol 196, 901-917). For the ease of reading, the CDR regions are called hereafter HCDR1, HCDR2, HCDR3 for the variable heavy chain and LCDR1, LCDR2, LCDR3 for the variable light chain.Table 5: CDRs regions of binders 1-5 according to IMGT and Chothia numbering systems.The present disclosure therefore encompasses an antibody (including a fragment or a variant thereof as previously defined) having:(i) a heavy chain comprising a variable heavy chain region (VH) of SEQ ID NO: 1186 and a light chain comprising a variable light chain region (VL) of SEQ ID NO: 1193;(ii) a heavy chain comprising a variable heavy chain region (VH) of SEQ ID NO: 1202 and a light chain comprising a variable light chain region (VL) of SEQ ID NO: 1209;(iii) a heavy chain comprising a variable heavy chain region (VH) of SEQ ID NO: 1143 and a light chain comprising a variable light chain region (VL) of SEQ ID NO: 1150;(iv) a heavy chain comprising a variable heavy chain region (VH) of SEQ ID NO: 1218 and a light chain comprising a variable light chain region (VL) of SEQ ID NO: 1225.(v) a heavy chain comprising a variable heavy chain region (VH) of SEQ ID NO: 1234 and a light chain comprising a variable light chain region (VL) of SEQ ID NO: 1241.The present disclosure also encompasses an antibody (including a variant or fragment thereof) having the H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 and L-CDR3 of binders 1-5 as defined in the present disclosure notably in Table 5. Typically, it encompasses an antibody (including a variant or a fragment thereof) having:(i) the H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 and L-CDR3 of SEQ ID NOs: 1171-1173 (Chothia) or 1174-1176 (IMGT) and 1178-1080 (Chothia) or 1080-1093 (IMGT) respectively; (n) the H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 and L-CDR3 of SEQ ID NOs: 11871-1189 (Chothia) or 1190-1192 (IMGT) and 1194-1196 (Chothia) or 1197-1199 (IMGT) respectively; (m) the H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 and L-CDR3 of SEQ ID NOs: 1203-1205 (Chothia) or 1206-1208 (IMGT) and 1210-1212 (Chothia) or 1213-1215 (IMGT) respectively; (iv) the H-CDR1, H-CDR2, HCDR3, L-CDR1, L-CDR2 and L-CDR3 of SEQ ID NOs: 1219-1221 (Chothia) or 1222-1224 (IMGT) and 1226-1228 (Chothia) or 1229-1231 (IMGT) respectively; (v) theH-CDRl,H-CDR2, HCDR3, L-CDR1 , L-CDR2 and L-CDR3 of SEQ ID NOs: 1235-1237 (Chothia) or 1238-1240 (IMGT) and 1242-1244 (Chothia) or 1245-1248 (IMGT) respectively.In some embodiments, a variant of binders 1-5 has:(i) a heavy chain comprising a variable heavy chain region (VH) having at least 95% identity with SEQ ID NO: 1170 and a light chain comprising a variable light chain region (VL) has at least 95% identity with SEQ ID NO: 1170;(ii) a heavy chain comprising a variable heavy chain region (VH) having at least 95% identity with SEQ ID NO: 1186 and a light chain comprising a variable light chain region (VL) has at least 95% identity with SEQ ID NO: 1193;(iii) a heavy chain comprising a variable heavy chain region (VH) having at least 95% identity with SEQ ID NO: 1202 and a light chain comprising a variable light chain region (VL) has at least 95% identity with SEQ ID NO: 1209;(iv) a heavy chain comprising a variable heavy chain region (VH) having at least 95% identity with SEQ ID NO: 1218 and a light chain comprising a variable light chain region (VL) has at least 95% identity with SEQ ID NO: 1225;(v) a heavy chain comprising a variable heavy chain region (VH) having at least 95% identity with SEQ ID NO: 1234 and a light chain comprising a variable light chain region (VL) has at least 95% identity with SEQ ID NO: 1241.The present disclosure also includes variants of binders 1-5 as above defined, wherein one or more of the H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2, and L-CDR3 has at least 60, 70, 80, 90, 95, 96, 97, 98, 99 or 100 percent identity with the corresponding H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2, and L-CDR3 of the parent binder 1-5 disclosed herein. Typically, as per the present disclosure, a variant may have between 1 , 2, 3 or 4 amino acid variations (including deletion, insertion or substitution) in one or more CDRs, as compared to the CDR sequence of the parent binder. In some embodiments, the variant has one or more of the H-CDR1 , H-CDR2, L-CDR1 , L-CDR2, and L-CDR3, notably one or more of the L-CDR1, L-CDR2, L-CDR3 that has at least 60, 70, 80, 90, 95, 96, 97, 98, 99 or 100 percent identity with the corresponding H-CDR1, H-CDR2, L-CDR1, L-CDR2, and L-CDR3, notably with the L-CDR1, L-CDR2, L-CDR3 of parent binder. By “bind a molecular complex comprising a peptide of SEQ ID NO:1034 and an HLA A*03:01 molecule as previously defined” it is typically intended that an ABP of the present invention, and notably an antibody (including a fragment or a variant thereof) as structurally defined above exhibits one or more of the functional properties as previously defined, which includes specificity and selectivity for the target molecular complex of the present disclosure as well as in some embodiments, the ability to drive effector cell activation and / or cytotoxic cell-mediated killing of target cells as previously defined.A variant of binders 1-5 further typically retains the functional properties of the parent binder from which it derives. In particular, a variant of binders 1-5 retains at least about 50%, 60%, 70%, 80%, 90%, 95% or 100% of the affinity / avidity and / or the specificity / selectivity of the parent binders and in some cases such a monoclonal antibody of the present invention may be associated with greater affinity, selectivity and / or specificity than the parent binder.Functional properties of an ABP of the present disclosure have been detailed previously. Some of them are summarized in the present section but should not be taken in a limited manner. Briefly, an ABP of the present disclosure (including binders 1-5 and variants thereof as structurally defined above) typically binds a target molecular complex as previously defined, in particular a complexcomprising a peptide of SEQ ID NO:1034 and an HLA A*03:01 molecule with a dissociation constant (Ka) of about 10'6M or less, 10'7M or less, 10'8M or less, 10'9M or less, IO'10M or less, or 10'11M or less. In some embodiments, the Kd is comprised between about 10'6M and 10'12M, notably between about 10'7M and 10'12M, between about 10'8M and 10'12M, between about 10'7M and 10'11M, between about 10'7M and IO'10M, between about 10'8M and IO'10M, between about 10'8M and 10'12M, between about 10'8M and 10'11M, between about 10'9M and 10'12M, or between about 10'9M and 10'11M. Typically, the Ka is comprised between 10'3pM and 50 nM, notably between 0.1 pM and 50 nM, notably between 0.1 pM and 5 nM, or between 1 pM and 10 nM notably between 1 pM and 5 nM, between 10 pM and 5 nM, between 0.1 nM and 50nM or between 0.1 nM and 10 nM, or between 1 nM and 50 nM, notably between 1 nM and 10 nM. Typically, the ABP (including binders 1-5 and variants thereof as structurally defined above) binds to the target molecular complex as previously defined with at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold or more greater affinity than to a non-target molecular complex comprising an off-target peptide and / or an MHC molecule that differs from the MHC molecule of the target molecular complex.Typically, the ABP (including binders 1-5 and variants thereof as structurally defined above) has a Ka for the molecular complex as previously defined, or a polypeptide comprising thereof that is at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold or less than its KDfor a non-target molecular complex comprising an off-target peptide and / or an MHC molecule that differs from the MHC molecule of the target molecular complex.Typically, the ABP (including binders 1-5 and variants thereof as structurally defined above) not bind to the HLA molecule in the absence of the matched HLA-restricted peptide (MAP). In some embodiments, the binders 1-5 do not bind the MAP in the absence of the matched HLA molecule. Typically, the binders 1-5 bind a molecular complex as herein defined comprising a peptide as herein disclosed in association with a matched MHC molecule when the complex naturally is presented at a cell surface, in particular when the complex is presented at the surface of a tumor cell.TCR-based ABPsIn some embodiments, the present disclosure provides a T cell receptor (TCR) or a variant thereof capable of interacting with, or binding to, a target molecular complex as herein described (e.g. a MAP encoded by a transcript of the gene NIHCOLE such as a transcript of table 2, a fragment or a variant thereof, or a peptide comprising a portion of any one of the sequences of table 3 and variants thereof, or a MAPs as disclosed in table 4 or a variant thereof) and an MHC molecule. In someembodiments, the present disclosure encompasses a T cell receptor (TCR) or a variant thereof capable of interacting with, or binding to a peptide of SEQ ID NO: 1034 or a variant thereof in association with an HLA A*03:01 or an HLA A* 11:01 molecule (i.e. a molecular complex comprising a peptide of SEQ ID NO: 1034 or a variant thereof in association with an HLA A*03:01 or an HLA A* 11:01 molecule).A TCR according to the present disclosure is typically capable of specifically interacting with or binding a molecular complex expressed at the surface of a living cell in vitro or in vivo.The term TCR as used herein refers to an immunoglobulin superfamily member having a variable binding domain, a constant domain, a transmembrane region, and a short cytoplasmic tail; see, e.g., Janeway et al, Immunobiology: The Immune System in Health and Disease, 3rd Ed., Current Biology Publications, p. 4:33, 1997) capable of specifically binding to an antigen peptide bound to a MHC receptor. A TCR can be found on the surface of a cell. The TCR-CD3 complex is composed of a genetically-diverse o.p, or y8 chains TCR heterodimer in noncovalent association with invariant CD3 dimers: CD3ey, CD3c8, and CD3i The a and P chains of the TCR heterodimer each contain an immunoglobulin (Ig)-like extracellular variable (V) and constant (C) domain, a membrane-proximal connecting peptide (CP), a single transmembrane (TM) region, and a short cytoplasmic tail. The variable domains of the TCR a-chain and P-chains have three hypervariable or complementarity-determining regions (CDRs) and binds to a peptide / MHC (pMHC) complex. Similarly, each subunit of the CD3ey and CD3e8 heterodimers comprises a single extracellular Ig-like domain, a CP, a TM region, and a long cytoplasmic tail. CD3^ has a short extracellular segment attached to CP, TM, and cytoplasmic regions. The TCR-CD3 complex exists on the T-cell surface in...

Claims

CLAIMS1. An isolated polypeptide comprising one or more target amino acid sequence(s) having at least 8 amino acid residues and which is characterized as follow:the target amino acid sequence is encoded by a nucleic acid molecule derived from the gene NIHCOLE as referenced in Table 1;the target amino acid sequence is encoded by a nucleic acid comprising a sequence of any one of SEQ ID NO: 1-55, a fragment or a variant thereof;the target amino acid sequence is of any one of SEQ ID NO:56-1032, a fragment or a variant thereof; orthe target amino acid sequence is of any one of SEQ ID NO: 1033-1140, or a variant thereof.

2. A polypeptide according to claim 1, wherein the polypeptide comprises a sequence of 8 to 15 amino acid residues, notably 8 to 12 amino acids residues which binds to an MHC molecule with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM; optionally wherein the polypeptide is a recombinant or synthetic polypeptide;optionally wherein, the target amino acid sequence does not derive from a sequence of the gene NIHCOLE that is not unique and / or that is also annotated as transposable element, notably the target amino acid sequence does not derive from the LINE repeat element L1PA2 located at chr5: 103,410,064-103,416,082 (GRCh37);optionally wherein, the polypeptide comprises a sequence that is encoded by a splice variant transcript of the NIHCOLE gene or a fragment thereof, and which comprises the junction of coordinates chr5: 103,416,742-103,417,581 forward strand (GRCh37),optionally wherein the polypeptide comprises one or more of the sequences SEQ ID NO: 72, 332, 405, 455, 555, 578, 734 948, 1005, 1029, and 1008, notably the sequences SEQ ID NO:72, 332, 405, 555, and 948, a fragment or a variant thereof, more particularly wherein the polypeptide comprises the sequence of SEQ ID NO: 1034, 1064, 1081, 1089, 1090 1101, 1016, 1109, 1120 and 1131, or variants thereof notably of SEQ ID NO: 1034, 1064, 1089, 1101 and 1131 or variants thereof.

3. A molecular complex comprising an MHC associated peptide (MAP) having a sequence of 8 to 15 amino acid residues from a polypeptide as defined in any one of claims 1 or 2 and an MHC type I molecule, wherein the polypeptide binds to the said MHC molecule with aKDbinding affinity of 10'6M or less or with an IC50 of less than 500 nM;optionally wherein the molecular complex comprises an HLA-A*03 or an HLA-A*11 molecule and a MAP of 8 to 15 amino acids residues (i) comprising the amino acid sequence of any one of SEQ ID NO: 1034 or 1064 or a variant thereof, and (ii) binding to the said HLA-A*03 and / or an HLA-A*011 molecule with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM; optionally wherein the MAP consists in SEQ ID NO: 1034 or 1064;optionally wherein the molecular complex comprises an HLA-A*02 molecule and a MAP of 8 to 15 amino acids residues (i) comprising the amino acid sequence of any one of SEQ ID NO: 1089, 1101, and 1131 or a variant thereof, and (ii) binding to the said HLA-A*02 with a KDbinding affinity of 10'6M or less or with an IC50 of less than 500 nM; optionally wherein the MAP consists in one of SEQ ID NOs: 1089, 1101 and 1131;optionally wherein, the HLA molecule and the peptide are operatively linked through a peptide bond, or through van der Waals forces;optionally wherein the HLA molecule and / or the peptide is conjugated to a detection tag; optionally wherein at least two peptide-MHC complexes are operatively linked to each other.

4. A cell expressing at his cell surface a polypeptide according to any one of claim 1 or 2, and / or a molecular complex according to claim 3;optionally wherein the cell is a cell line, notably a cancer cell line; optionally wherein the cell is an antigen presentation cell (APC), notably a dendritic cell, optionally wherein the APC is in vitro isolated; optionally wherein the peptide and / or the HLA molecule of the HLA complex is recombinantly expressed.optionally wherein the cell is an antigen presenting cell (APC) expressing at its cell surface one or more MAP(s) having a sequence of 8 to 15 amino acid residues from a polypeptide as defined in any one of claim lor 2, optionally wherein the APC has been pulsed with the said one or more MAP or wherein the APC has been transfected with the said or more MAP(s), optionally wherein the APC is expressing one or more MHC molecule that bind with the said one or more MAP with a KDbinding affinity of 10'6M or less or an IC50 of less than 500 nM; optionally wherein the APC is a dendritic cells.

5. An antigen binding protein (ABP) that specifically binds a polypeptide according to any one of claim 1 or 2, optionally in association an MHC molecule with a KDbinding affinity of 10'6M or less or with an IC50 of less than 500 nM and / or with a molecular complex according to claim 3; optionally wherein the ABP essentially consists in an antibody, a TCR or a variant thereof; wherein the said ABP binds the said polypeptide or molecular complex with a KDbinding affinity of 10'6M or less, preferably comprised between 0.1 to 100.1 O'9M;optionally wherein the ABP comprises light chain CDRs (LCDR1-3) and heavy chain CDRs (HCDR 1-3) as defined in Table 4:optionally wherein the ABP comprises (i) aVLof SEQIDNO: 1091 andaVHofSEQIDNO:1084; (n) a VL of SEQ ID NO: 1112 and a VH of SEQ ID NO: 1105; (hi) a VL of SEQ ID NO: 1129 and a VH of SEQ ID NO: 1122; (iv) a VL of SEQ ID NO: 1150 and a VH of SEQ ID NO: 1143; (v) a VL of SEQ ID NO: 1167 and a VH of SEQ ID NO: 1160 as defined in Table 5;optionally wherein the ABP comprises an scFv of any one of SEQ ID NO: SEQ ID NO: 1092, 1113, 1130, 1152 or 1168;optionally wherein the ABP is a multispecific antibody, a CAR or an antibody drug conjugate (ADC); optionally wherein the multispecific antibody is a T cell engager (TCE) or an NK cell engager (NKCE); optionally wherein the ABP is a chimeric TCR;optionally wherein the ABP is a tetravalent bispecific antibody construct, optionally wherein the antibody construct is selected from an LC appended IgG or a tandem scFv fused to a Fc domain, wherein the Fc domain of the IgG or the tandem scFv-Fc fusion is a silent Fc domain.

6. A nucleic acid encoding a polypeptide according to any one of claim 1 or 2, optionally wherein the nucleic acid comprises or consists of any one of SEQ ID NOs: 1-55, a fragment or a variant thereof; optionally wherein the nucleic acid comprises or consists of any one of consensus transcripts encoding any one of the polypeptides of SEQ ID NO: 72, 332, 405, 555 and 948, or an ABP according to claim 5.

7. A vector comprising a nucleic acid according to claim 6.

8. A cell comprising a nucleic acid and / or a vector according to claim 6 or 7; optionally wherein the cell is an immune cell;optionally wherein the nucleic acid is encoding a polypeptide according to claim 1 or 2 and wherein the cell is an antigen presenting cell (APC);optionally wherein the nucleic acid is encoding an ABP according to claim 5 and wherein the immune cell is selected from sub-types and subpopulations of T cells notably of CD4+ T cells, CD8+ T cells (including alpha / beta T cells and gamma / delta T cells), CD4+ and CD8+ T cells, T regulatory cells (Treg), Naive T cells (TN cells), effector T cells, memory stem T cells (TSCMs), memory T cells (TCMs), effector memory T cells (TEM cells), resident memory T cells (TCRMs), mucosa-associated invariant T (MAIT) cells, and NK T cells (NKT cells), iPSC-derived T cells, or T cells derived from adipose derived stem cells (ADSCs).

9. A composition comprising a polypeptide according to claim 1 or 2, a molecular complex according to claim 3, a cell according to claim 4 or 8, an ABP according to claim 5, a nucleic acidaccording to claim 6, or a vector according to claim 7; optionally wherein the composition is a pharmaceutical composition; optionally wherein the composition is an immunogenic or vaccine composition; optionally wherein the composition comprises at least one pharmaceutical adjuvant and / or a carrier.

10. A therapeutic agent consisting in a polypeptide according to claim 1 or 2, a molecular complex according to claim 3, a cell according to claim 4 or 8, an ABP according to claim 5, a nucleic acid according to claim 6, a vector according to claim 7, a composition according to claim 9, or a combination thereof for use as a medicine; optionally for use as a medicine in the treatment of a patient suffering from a cancer or a tumor; optionally wherein the cancer or the tumor is a solid cancer or tumor; optionally wherein the solid cancer or tumor is selected from a lung tumor or cancer, a gastro-intestinal cancer or tumor, or an ovarian cancer or tumor;optionally wherein the cancer or tumor is positive for the expression a polypeptide according to any one of claims 1-5 or a polynucleotide encoding thereof, optionally wherein the subject has been determined to have a cancer that is positive for expression of the said polypeptide or polynucleotide encoding thereof, optionally wherein the polypeptide or a fragment thereof comprises a amino acid sequence that binds an HLA A* 02, A* 03, and / or A* 11 molecule and wherein the patient is selected, or known, to express one or more of the said HLA molecules .

11. Use of a polypeptide according to any one of claim 1 or 2, optionally in association an MHC molecule with a KD binding affinity of 10'6M or less or with an IC50 of less than 500 nM, or a molecular complex according to claim 3, for the screening of a binding protein or for assessing the specificity of a binding protein targeting thereof; optionally wherein, the binding protein is selected or considered as specific for the said target polypeptide and / or molecular complex when its binds to the said target polypeptide and / or molecular complex with a KDbinding affinity of 1 O'6M or less, preferably comprised between 0.1 to 100 1 O'9M;optionally wherein, the screening comprises the steps of:contacting the antigen-binding protein with the said target polypeptide and / or target molecular complex, optionally wherein the said target polypeptide and / or complex is linked to a solid support or presented at a cell surface, andrecovering the antigen-binding protein which is bound to the said target polypeptide and / or complex; optionally wherein steps a) and b) are repeated one or more times.optionally, wherein the screening comprises one or more steps for assessing cross-reactivity against one or more counter-selection peptides;optionally wherein when the peptide is of SEQ ID NO: 1034 or a variant thereof, one or counterselection peptides are chosen among peptides of 10 to 12 amino acid residues, that bind an HL A A3 and / or Al 1 molecule with an IC50 of 500 nM or less and have at least 50 % similarity with the said sequence SEQ ID NO: 1034 ; optionally wherein the counter selection peptide are known to be expressed in normal tissue; optionally wherein one or more counter selection peptides are chosen among the sequences of SEQ ID Nos: 1264-1270.optionally wherein the ABPs does not cross react or reacts less than 20 %, notably less than 15%, less than 10%, or less than 5 % of the levels of the target peptide MHC molecular complex with a molecular complex comprising a similar peptides from a protein or a peptide that is expressed in healthy tissues, optionally wherein any cytotoxic response to said molecular complex comprising a similar peptides from a protein or a peptide that is expressed in healthy tissues is less than 30%, notably less than 20 %, notably less than 10 %, notably less than 5 % of the cytotoxic response obtained with the target molecular complex;optionally, wherein any cytotoxic response to the binding of said counter selection peptide in association to a cytotoxic immune cell is less than 30%, notably less than 20 %, notably less than 10 %, notably less than 5 % of the cytotoxic response obtained with the target polypeptide and / or molecular complex,12. An in vitro or ex vivo method of determining whether a subject has cancer or is at risk of a cancer, the method comprising detecting the presence and / or amount of a polypeptide according to any one of claim 1 or 2 and / or a nucleic acid encoding thereof, notably a nucleic acid according to claim 6, in a biological sample harvested from the subject; optionally, wherein detection of the said polypeptide and / or polynucleotide means that the patient has a cancer; optionally wherein the method comprises determining the amount of the said polypeptide or nucleic acid and comparing it to a reference value, wherein the subject is determined to have a cancer if the determined expression level is equal or superior to the reference value.optionally wherein the method further comprises selecting a treatment regimen based upon the detected presence or amount of peptide and / or nucleic acid encoding thereof;optionally wherein the treatment comprises a therapeutic agent as defined in claim 10; optionally, wherein the biological sample is a tissue, a blood sample, a cell line, an organoid, saliva, cerebrospinal fluid, or other bodily fluids harvested from the subject;optionally, wherein the sample is a tumor or cancer sample.

13. An in vitro or ex vivo method for identifying a cancer patient as likely to benefit from a treatment a therapeutic agent as defined in claim 10 , said method comprising a step of detectingthe expression of a polypeptide according to any one of claim lor 2 a and / or nucleic acid encoding thereof, notably a nucleic acid according to claim 6 in a tumor sample from the subject, wherein the patient is likely to benefit from the treatment with the said therapeutic if the peptide and / or nucleic acid encoding thereof is detected in the said tumor sample; optionally, wherein the polypeptide or a fragment thereof comprises a amino acid sequence that binds an HLA A*02, A*03, and / or A*11 molecule and wherein the patient is selected or known to express one or more of the said HLA molecules .

14. An in vitro or ex vivo method for prognosing a patient or for detecting T cell responses in a patient, the method comprising: contacting a biological sample from the patient with the polypeptide optionally in association with an MHC molecule as defined in any one of claim 1 or 2 or with the molecular complex according to claim 3 ; optionally, wherein detecting T cell responses comprises detecting the binding of the said polypeptide or molecular complex to the T cell or TCR; optionally, wherein the polypeptide or a fragment thereof comprises a amino acid sequence that binds an HLA A*02, A*03, and / or A*11 molecule, notably an amino acid sequence of any one of SEQ ID NO: 1034, 1064, 1089, 1101 or 1131, and wherein the patient is selected or known to express one or more of the said HLA molecules .

15. The methods and uses according to of any one of claims 12-14, wherein the presence or amount of the target polypeptide as defined in any one of claim 1 or 2 and / or of a polynucleotide encoding thereof, notably a nucleic according to claim 3 is determined using an NGS-based assay, a nucleic acid amplification assay, an issue hybridization assay, an immuno-assay, a mass spectrometrybased assay, or a combination thereof;optionally, wherein the cancer or tumor is a solid tumor, notably a gastro-intestinal cancer or tumor, a lung cancer or tumor or an ovarian cancer or tumor.

16. A kit for detecting the presence of a peptide as defined in any one of claim 1 or 2, or a nucleic acid encoding thereof, notably a nucleic acid according to claim 6 in a biological sample, or for use in a method according to claim 12-15, the kit comprising:a labeled compound or agent capable of detecting the peptide or nucleic acid in the biological sample;optionally means for determining the amount of peptide or nucleic acid encoding thereof in the biological sample; andoptionally means for comparing the amount of the polypeptide or nucleic acid encoding thereof in the biological sample with a standard;optionally the compound or agent is packaged in a suitable container; optionally the kit further comprises instructions for using the kit to detect the polypeptide of transcript encoding thereof. optionally, the one or more label compounds comprise one or more nucleic acid sequence(s) comprising a nucleotide sequence of any one of Table 11 or 15 and / or one or more polynucleotide sequence(s) comprising a nucleotide sequence that specifically hybridizes any one of the sequences of Table 12.

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