Anti-human ICOS antibodies for use in immunohistochemistry (IHC) protocols and for diagnosing cancer

Abstract

In alternative embodiments, chimeric, synthetic, or recombinant anti-human ICOS protein or polypeptide (also referred to as inducible T-cell costimulatory molecule, or cluster of differentiation 278, or CD278) antibodies (Abs) are provided, including, for example, articles of manufacture and kits comprising same, and methods for making and using same, including their use in the detection or diagnosis and treatment of cancer or other diseases or conditions involving ICOS expression. In alternative embodiments, the anti-ICOS proteins (e.g., antibodies) provided herein are used in conjunction with agents to determine whether ICOS expression or activity is present, increased, decreased, or absent. In alternative embodiments, the anti-ICOS antibodies provided herein are used in the diagnosis and / or treatment of cancer or tumors.

Description

[Technical Field]

[0001] [Related Applications] This PCT international patent application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. (USSN) 63 / 409,076, filed September 22, 2022. The above-referenced application is incorporated herein by reference in its entirety for all purposes.

[0002] [Technical field] The present invention generally relates to immunohistochemistry (IHC) and cancer diagnosis and treatment. In alternative embodiments, chimeric, synthetic, or recombinant anti-human ICOS protein or polypeptide (also referred to as inducible T-cell costimulatory molecule, or cluster of differentiation 278, or CD278) antibodies (Abs) are provided, including, for example, products and kits containing same, and methods for producing and using same, including their use in the detection or diagnosis and treatment of cancer or other diseases or conditions involving ICOS expression. In alternative embodiments, the anti-ICOS proteins (e.g., antibodies) provided herein are used in conjunction with agents to determine whether ICOS expression or activity is present, increased, decreased, or absent. In alternative embodiments, the anti-ICOS antibodies provided herein are used in the diagnosis and / or treatment of cancer or tumors, such as carcinoma (optionally squamous cell carcinoma), breast cancer, colon cancer or colorectal cancer, melanoma (optionally malignant melanoma) or multiple myeloma, plasmacytoma, lymphoma, bladder or urothelial cancer, cervical cancer, ovarian cancer, esophageal cancer or esophageal squamous cell carcinoma; malignant pleural mesothelioma, prostate cancer, microsatellite instability-high / mismatch repair deficient tumors, human papillomavirus-positive or Epstein-Barr-positive tumors, hepatocellular carcinoma or liver cancer, lung cancer (optionally non-small cell lung cancer (NSCLC)), gastric cancer, renal or kidney cancer, pancreatic cancer, breast cancer (optionally triple-negative breast cancer), lymphoma or leukemia, or mycosis fungoides. [Background technology]

[0003] The ICOS protein, also known as inducible T cell costimulatory molecule, or cluster of differentiation 278, or CD278, is a member of the CD28 and CTLA-4 cell surface receptor family. ICOS forms homodimers and plays an important role in regulating intercellular signaling, immune responses, and cell proliferation. ICOS is a costimulatory receptor for T cell enhancement.

[0004] ICOS + T cells are found in tumor tissue and ICOS + Anti-CTLA-4 treatment in tumor-bearing mice resulted in tumor rejection in 80%–90% of subjects, whereas efficacy was less than 50% in gene-targeted mice lacking ICOS or its ligand (ICOSLG).

[0005] ICOS activation may enhance the effects of inhibitory checkpoint blockade, whereas its neutralization could reduce the function of immunosuppressive Tregs and inhibit lymphoid tumor cells expressing Tfh markers.

[0006] Vopratelimab (JTX-2011) is an investigational humanized IgG1κ agonist mAb designed to specifically bind ICOS and enhance antitumor immune responses. The mechanism of action of vopratelimab requires initial priming of T cells followed by upregulation of ICOS expression on the cell surface of CD4 T cells; subsequent vopratelimab engagement results in T cell proliferation and sustained activation. Summary of the Invention

[0007] In an alternative embodiment, an isolated or purified antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) capable of specifically binding to human ICOS (inducible T-cell costimulatory molecule) protein or human CD278 polypeptide is provided, wherein the isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, (a) the following sequence: (1) an amino acid sequence comprising the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO: 1, or CDR1 amino acid (aa) residues GFSLSSYG (residues 25-32 of SEQ ID NO: 1), CDR2 aa residues INSDHST (residues 50-56 of SEQ ID NO: 1), and CDR3 aa residues ARSYGIGSIF (residues 93-102 of SEQ ID NO: 1); or (2) an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98% sequence identity, or about 70% to 100% sequence identity, to each of the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO: 1, or to CDR1 amino acid (aa) residues GFSLSSYG (residues 25-32 of SEQ ID NO: 1), CDR2 aa residues INSDHST (residues 50-56 of SEQ ID NO: 1), and CDR3 aa residues ARSYGIGSIF (residues 93-102 of SEQ ID NO: 1), or (3) An amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, or 98% sequence identity to SEQ ID NO: 1, or about 70% to 100% sequence identity to SEQ ID NO: 1, or an amino acid sequence having complete sequence identity to SEQ ID NO: 1. a heavy chain variable region (VH) comprising: (b) the following sequence: (1) an amino acid sequence comprising the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO: 2, or CDR1 amino acid (aa) residues KSVYNNNQ (residues 27-34 of SEQ ID NO: 2), CDR2 aa residues EAF (residues 52-54 of SEQ ID NO: 2), and CDR3 aa residues AAVYSDDSDNS (residues 91-101 of SEQ ID NO: 2); or (2) an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98% sequence identity, or about 70% to 100% sequence identity, to each of the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO: 2, or to CDR1 amino acid (aa) residues KSVYNNNQ (residues 27-34 of SEQ ID NO: 2), CDR2 aa residues EAF (residues 52-54 of SEQ ID NO: 2), and CDR3 aa residues AAVYSDDSDNS (residues 91-101 of SEQ ID NO: 2), or (3) An amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, or 98% sequence identity to SEQ ID NO: 2, or about 70% to 100% sequence identity to SEQ ID NO: 2, or an amino acid sequence having complete (100%) sequence identity to SEQ ID NO: 2. a light chain variable region (VL) comprising: (c) the heavy chain variable region (VH) of (a) and the light chain variable region (VL) of (b) Includes.

[0008] In alternative embodiments of the isolated or purified antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) provided herein: - isolated or purified antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP), antigen-binding fragments (Fab, or Ab fragments having only one constant domain and one variable domain of each of the Ab heavy and light chains); F(ab')2 (or Ab that is digested by pepsin to generate two fragments: F(ab')2 fragment and pFc' (pepsin-cleavable Fc) fragment); Fab' (single chain F(ab')2 fragment), single-chain variable fragments (scFv) (or fusion proteins of the variable regions of the Ab heavy and light chains, optionally linked together using a linker peptide of about 10 to about 25 amino acids in length); (scFv)2, or di-scFv or bi-scFv, or a single peptide chain having two variable heavy chain regions and two variable light chain regions to give a tandem scFv, minibodies (or fusion proteins of Ab heavy and light chain variable regions linked together using alkyl groups, optionally methyl or ethyl groups); diabodies (or scFvs with a linker peptide (optionally about 5 amino acids) that is too short for the two variable regions to fold together, thereby forcing the scFv to dimerize), triabodies or tetrabodies (or scFvs with a linker peptide (optionally about 5 amino acids) that is too short for the two variable regions to fold together, thereby forcing the scFv to trimerize or tetramerize), single domain antibodies (dABs) (or single variable regions of Ab heavy or Ab light chains); multiple complementarity-determining region (CDR) fragments, or Multispecific antibodies formed from two or more antibody fragments produced as or in the form of; - if present, the heavy chain variable region (VH) Amino acid sequence: QSLEESGGRLVTPGTPLTLTCTVS GFSLSSYG VSWVRQAPGKGLEWIGI INSDHST YYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFC ARSYGIGSIF WGPGTLVTVSS (SEQ ID NO: 1), or comprising SEQ ID NO: 1 with one or more amino acid substitutions, additions (insertions) or deletions, and wherein the recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP retains its ability to specifically bind to a human ICOS protein or polypeptide; - the one or more amino acid substitutions in the heavy chain variable region (VH) comprise one or more conservative amino acid substitutions, and optionally the one or more conservative amino acid substitutions comprise: a substitution of an aliphatic amino acid with another aliphatic amino acid; a substitution of serine with threonine or vice versa; a substitution of an acidic residue with another acidic residue; a substitution of a residue bearing an amide group with another residue bearing an amide group; an exchange of a basic residue with another basic residue; or a substitution of an aromatic residue with another aromatic residue; - the heavy chain variable region further comprises at least a portion of a heavy chain constant region, and optionally, the heavy chain constant region has the amino acid sequence: GQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 3); - the heavy chain has the sequence: QSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLVTVSSGQP KAPSVFPLAPCCGDTPSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIF PPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 4); - the heavy chain variable region comprises an amino acid terminal signal sequence, and optionally, the heavy chain variable region amino acid terminal signal sequence comprises the sequence METGLRWLLLVAVLKGVQC (SEQ ID NO: 5); - the heavy chain variable region with a signal sequence has the sequence METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLVTVSS (SEQ ID NO: 6), or The heavy chain, comprising variable and constant domains and having a signal sequence, has the sequence: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYG IGSIFWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCS comprising KPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 7); - if present, the light chain variable region (VL) (a) Amino acid sequence: AAVLTQTPSPVSAAVGGTVSISCQSS KSVYNNNQ LSWFQQKPGQRPKLLIY EAF KLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYC AAVYSDDSDNS FGGGTEVVVK (SEQ ID NO: 2), or comprising SEQ ID NO:2 having one or more amino acid substitutions, additions (insertions) or deletions, and wherein the recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP retains its ability to specifically bind to a human ICOS protein or polypeptide; - the one or more amino acid substitutions in the light chain variable region (VL) comprise one or more conservative amino acid substitutions, and optionally the one or more conservative amino acid substitutions comprise a conservative substitution comprising: substitution of an aliphatic amino acid with another aliphatic amino acid; substitution of serine with threonine or vice versa; substitution of an acidic residue with another acidic residue; substitution of a residue bearing an amide group with another residue bearing an amide group; exchange of a basic residue with another basic residue; or substitution of an aromatic residue with another aromatic residue; - the light chain variable region further comprises at least a portion of a light chain constant region, and optionally, the light chain constant region has the amino acid sequence: GDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 8); - the light chain has the sequence: AAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 9); - the light chain variable domain further comprises an amino-terminal signal sequence, and optionally, the amino-terminal signal sequence of the light chain variable domain comprises the sequence MDTRAPTQLLGLLLLWLPGATF (SEQ ID NO: 10); - a light chain variable domain with a signal sequence, MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVK (SEQ ID NO: 11), or - the light chain with a signal sequence comprising MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 12); - SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, and / or SEQ ID NO:12 have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 conservative amino acid substitutions, and the recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, retains its ability to specifically bind to a human ICOS protein or polypeptide; - the heavy chain constant region comprises an amino acid sequence derived from an IgG, IgM, IgA, IgD or IgE isotype, or the light chain constant region comprises an amino acid sequence derived from a kappa (κ) or lambda (λ) isotype; - at least a portion of the heavy chain constant region, at least a portion of the light chain constant region, or at least a portion of the heavy chain constant region and the light chain constant region is or comprises an amino acid sequence of human, rabbit, mouse or rat origin, or comprises a constant region amino acid sequence derived from human, rabbit, mouse or rat; - at least a portion of the heavy chain constant region, at least a portion of the light chain constant region, or at least a portion of the heavy chain constant region and the light chain constant region is or comprises a synthetic amino acid sequence; - the recombinant Ab, its Ag-binding fragment, or monomeric or dimeric ABP, or the heavy chain constant region, or the light chain constant region, or the heavy chain constant region and the light chain constant region further comprises or is bound to a heterologous protein, peptide, or compound or composition, and optionally the heterologous protein or peptide, or compound or composition comprises a detectable protein, detectable agent or binding moiety; and optionally the heterologous protein or peptide comprises a carrier protein, or the heterologous protein, peptide, or compound or composition is covalently conjugated to the recombinant antibody (Ab), or Ag-binding fragment thereof, or monomeric or dimeric ABP; the detectable agent or binding moiety comprises biotin, a fluorescent or chemiluminescent label, a fluorophore, perylene, fluorenyl, coumarin, 7-methoxycoumarin (Mca), 4-(dimethylaminoazo)benzene-4-carboxylic acid (dabcyl), Tamra, boron-dipyrromethene (BODIPY), or derivatives thereof, a dye, a radioisotope, a quantum dot or photoluminescent aqueous nanocrystal, a hapten, or an antibody binding epitope or domain; optionally, the dye is rhodamine, [2-(4-nitro-2,1,3-benzoxadiazol-7-yl)aminoethyl]trimethylsilyl; and / or wherein the hapten is or comprises a biotin, theophylline, digoxigenin, carborane, fluorescein, or bromodeoxyuridine moiety; and / or - the Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, is a recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, or comprises a peptide or polypeptide produced by recombinant techniques.

[0009] In alternative embodiments, chimeric or recombinant nucleic acids are provided that comprise or consist of nucleic acid sequences encoding the Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs provided herein.

[0010] In an alternative embodiment of the chimeric or recombinant nucleic acids provided herein, - the chimeric or recombinant nucleic acid further comprises and is operably linked to a transcriptional regulatory element, and optionally the transcriptional regulatory element comprises a promoter, and optionally the promoter is an inducible promoter or a constitutive promoter; and / or - the chimeric or recombinant nucleic acid further comprises a sequence encoding an amino-terminal signal peptide, and optionally, the amino-terminal signal peptide comprises the amino acid sequence: METGLRWLLLVAVLKGVQC (SEQ ID NO: 5); or MDTRAPTQLLGLLLLWLPGATF (SEQ ID NO: 10).

[0011] In alternative embodiments, provided are expression cassettes, vectors, recombinant viruses, artificial chromosomes, cosmids, or plasmids comprising chimeric or recombinant nucleic acids provided herein, including nucleic acids encoding antibodies (Abs), or antigen (Ag)-binding fragments thereof, or monomeric or dimeric antigen binding proteins (ABPs) provided herein.

[0012] In alternative embodiments, provided are cells that comprise or have contained therein a chimeric or recombinant antibody or dimeric antigen-binding protein provided herein, a chimeric or recombinant nucleic acid provided herein, or an expression cassette, vector, recombinant virus, artificial chromosome, cosmid, or plasmid provided herein. In alternative embodiments of the cells provided herein, the cell is a bacterial, fungal, mammalian, yeast, insect, or plant cell; or the mammalian cell is a human cell.

[0013] In an alternative embodiment, (a) contacting a cell, tissue, or organ, or a portion of any of the foregoing, with at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP provided herein; and (b) detecting specific binding of at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, to a BCMA polypeptide within or on the surface of a cell, tissue or organ, or part of any of the above; thereby detecting the presence of human BCMA protein within or on the surface of a cell, tissue, organ, or part of any of the above. A method is provided for detecting the presence of human ICOS (inducible T-cell costimulatory molecule) protein, or human CD278 protein or polypeptide in or on the surface of a cell, tissue, organ, or part of any of the above, comprising:

[0014] In an alternative embodiment of the method for detecting the presence of human ICOS provided herein: - at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, comprises a variable heavy chain (VH) having an amino acid sequence comprising SEQ ID NO: 1 and a variable light chain (VL) having an amino acid sequence comprising SEQ ID NO: 2; - at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, comprises a heavy chain having an amino acid sequence comprising SEQ ID NO: 4 and a light chain having an amino acid sequence comprising SEQ ID NO: 9; - the method comprises (or further comprises) contacting a cell, tissue or organ, or a portion of any of the above, with two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs, or a mixture of two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs, and optionally, the contacting comprises the use of an immunohistochemistry (IHC) assay; - the method further comprises the step of contacting an Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, that specifically binds to human ICOS protein or human CD278 protein or polypeptide with a detectable agent, thereby indicating or conveying specific binding of the Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP to human ICOS protein or human CD278 protein or polypeptide, and optionally, the detectable agent specifically binds to the Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP; - the cell, tissue, organ or portion of any of the above is or comprises an early B cell, pro-B cell, pre-B lymphocyte, mature B lymphocyte, follicular center cell, or cell in a tonsil, organ, lymph node germinal center, bone marrow stem cell, bone marrow hematopoietic cell, lymphocyte, parafollicular T lymphocyte, subpopulation of parafollicular T lymphocyte, liver bile canalicular cell, renal glomerular cell, proximal tubule cell, breast myoepithelial cell, stromal cell around or associated with an invasive tumor cell, kidney cell, cerebellar cell, prostate cell, pancreatic cell, bone marrow cell or epithelial cell, and optionally the epithelial cell is a brain, lung, intestine, kidney, breast or placental epithelial cell, and optionally the organ is liver, prostate, brain, pancreas, bladder, colon, esophagus, kidney, skin or lung, and optionally the cell, tissue, organ or portion of any of the above is or comprises a cancer or tumor cell, or a cancer cell or carcinoid tumor cell; the cancer or tumor cell is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma cell or a leukemia cell, or a mycosis fungoides cell; and / or - the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma or mantle cell lymphoma, and optionally the B-cell lymphoma is Hodgkin's lymphoma, ... and optionally, the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL), and optionally, the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells.

[0015] In an alternative embodiment, a method is provided for detecting or diagnosing cancer or tumor, the method comprising detecting expression or presence of human ICOS (inducible T-cell costimulatory molecule) protein, or human CD278 protein or polypeptide in or on the surface of a cell, tissue or organ sample using the methods provided herein, and wherein detection of specific binding of an Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP to human ICOS (inducible T-cell costimulatory molecule) protein, or human CD278 protein or polypeptide within or on the surface of a cell, tissue or organ or portion of any of the above detects or diagnoses, or aids in the detection or diagnosis of, the cancer or tumor.

[0016] In an alternative embodiment of the method for detecting or diagnosing cancer or a tumor, - the cancer or tumor is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), or a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or an esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell derived from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer cell (optionally a non-small cell lung cancer (NSCLC) cell), a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma cell or a leukemia cell, or a mycosis fungoides cell; - the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma or mantle cell lymphoma, and optionally the B-cell lymphoma is Hodgkin's lymphoma, ... Hodgkin's lymphoma or non-Hodgkin's lymphoma, and optionally the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL), and optionally the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells; - the cell, tissue or organ sample is derived from an individual in need thereof or an individual who has a relatively high risk of having cancer or a tumor or has a family history of cancer or a tumor; - detecting comprises performing an immunohistochemistry (IHC) assay, and optionally, at least two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs are used to contact the cell, tissue or organ sample; - at least one of the two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs comprises a variable heavy chain (VH) having an amino acid sequence comprising SEQ ID NO: 1 and a variable light chain (VL) having an amino acid sequence comprising SEQ ID NO: 2; and / or - at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, comprises a heavy chain having an amino acid sequence comprising SEQ ID NO:4 and a light chain having an amino acid sequence comprising SEQ ID NO:9.

[0017] In alternative embodiments, methods are provided for treating, ameliorating, or preventing cancer or tumors, comprising first detecting or diagnosing the cancer or tumor using the methods provided herein, and then treating an individual in need thereof for the treatment, amelioration, or prevention of the cancer or tumor.

[0018] In an alternative embodiment of the methods for treating, ameliorating, or preventing cancer or tumors provided herein, - the cancer or tumor is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma cell or a leukemia cell, or a mycosis fungoides cell; - the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma or mantle cell lymphoma, and optionally the B-cell lymphoma is Hodgkin's lymphoma and / or the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells; and / or - the cell, tissue or organ sample is derived from an individual in need thereof, and optionally the individual in need thereof is an individual who has a relatively high risk of having tumor cancer or has a family history of cancer or tumors.

[0019] In an alternative embodiment, there is provided a use of at least one recombinant antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) provided herein, or encoded by a nucleic acid provided herein, for detecting or diagnosing, or treating, ameliorating, or preventing cancer.

[0020] In an alternative embodiment of the use provided herein, - the cancer or tumor is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma cell or a leukemia cell, or a mycosis fungoides cell; - the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma or mantle cell lymphoma, and optionally the B-cell lymphoma is Hodgkin's lymphoma and / or the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells; and / or - detecting includes performing an immunohistochemistry (IHC) assay.

[0021] In alternative embodiments, there is provided a recombinant antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP), for use in the detection or diagnosis of, or the treatment, amelioration, or prevention of, cancer. In alternative embodiments, the cancer or tumor is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon or colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma or leukemia cell, or a mycosis fungoides cell. In alternative embodiments, the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma or mantle cell lymphoma, and optionally B-cell lymphoma. In an alternative embodiment, the cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma, and optionally the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL), and optionally the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells. In an alternative embodiment, the detecting or diagnosing step comprises performing an immunohistochemistry (IHC) assay.

[0022] In alternative embodiments, kits are provided that include a chimeric or recombinant antibody provided herein; a chimeric or recombinant nucleic acid provided herein; or an expression cassette, vector, recombinant virus, artificial chromosome, cosmid, or plasmid provided herein; or a cell provided herein. In alternative embodiments of the kits provided herein, the kits include components required for an immunohistochemistry (IHC) assay and / or instructions for performing the methods provided herein.

[0023] The details of one or more exemplary embodiments of the invention are set forth in the accompanying drawings and description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0024] All publications, patents, and patent applications cited herein are expressly incorporated by reference in their entirety for all purposes.

[0025] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0026] The drawings presented herein are illustrations of exemplary embodiments provided herein and are not intended to limit the scope of the invention as encompassed by the claims. [Brief explanation of the drawings]

[0027] [Figure 1A]1 shows IHC images comparing an exemplary anti-human ICOS antibody (Ab) provided herein, also designated T0251A, having a heavy chain with an amino acid sequence comprising SEQ ID NO: 4 and a light chain with an amino acid sequence comprising SEQ ID NO: 9, with a reference anti-human ICOS Ab (Abscam, designated SP98) in IHC staining of tonsil cells, where the upper image is T0251A and the lower image is SP98. Like reference symbols in the various drawings indicate like elements. [Figure 1B] 1 shows IHC images comparing an exemplary anti-human ICOS antibody (Ab) provided herein, also designated T0251A, having a heavy chain with an amino acid sequence comprising SEQ ID NO: 4 and a light chain with an amino acid sequence comprising SEQ ID NO: 9, with a reference anti-human ICOS Ab (Abscam, designated SP98) in IHC staining of melanoma cells, where the upper image is T0251A and the lower image is SP98. Like reference symbols in the various drawings indicate like elements. [Figure 1C] 1 shows IHC images comparing an exemplary anti-human ICOS antibody (Ab) provided herein, also designated T0251A, having a heavy chain with an amino acid sequence comprising SEQ ID NO: 4 and a light chain with an amino acid sequence comprising SEQ ID NO: 9, with a reference anti-human ICOS Ab (Abscam, designated SP98) in IHC staining of liver cells, where the upper image is T0251A and the lower image is SP98. Like reference symbols in the various drawings indicate like elements. [Figure 1D] 1 shows IHC images comparing an exemplary anti-human ICOS antibody (Ab) provided herein, also designated T0251A, having a heavy chain with an amino acid sequence comprising SEQ ID NO:4; and a light chain with an amino acid sequence comprising SEQ ID NO:9, with a reference anti-human ICOS Ab (Abscam, designated SP98) in IHC staining of colonocytes, where the upper image is T0251A and the lower image is SP98. Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION OF THE INVENTION

[0028] In alternative embodiments, chimeric, synthetic, or recombinant anti-human ICOS protein (also called inducible T-cell costimulatory molecule, or cluster of differentiation 278, or CD278; activation-induced lymphocyte immunomodulatory molecule; AILIM; and CVID1)-binding polypeptides, including ICOS-binding antibodies (Abs), are provided, including articles of manufacture and kits comprising same, and methods for making and using same, including, for example, their use in the detection or diagnosis, and treatment, of cancer or other diseases or conditions involving expression of ICOS.

[0029] Although the present invention is not limited by any particular mechanism of action, in alternative embodiments, the antibodies or antigen binding proteins provided herein target (and specifically bind to) ICOS protein, which is expressed on the surface of cancer cells, as found in some types of cancer, such as cancer (optionally squamous cell carcinoma), breast cancer, colon cancer or colorectal cancer, melanoma (optionally malignant melanoma) or multiple myeloma, plasmacytoma, lymphoma, bladder or urothelial cancer, cervical cancer, ovarian cancer, esophageal cancer or esophageal squamous cell carcinoma; malignant pleural mesothelioma, prostate cancer, microsatellite instability-high / mismatch repair deficient tumors, human papillomavirus-positive or Epstein-Barr-positive tumors, hepatocellular carcinoma or liver cancer, lung cancer (optionally non-small cell lung cancer (NSCLC)), gastric cancer, renal or kidney cancer, pancreatic cancer, breast cancer (optionally triple-negative breast cancer), lymphoma or leukemia, or mycosis fungoides.

[0030] Expression of recombinant or chimeric antibodies In alternative embodiments, chimeric or recombinant Abs provided herein, including the exemplary chimeric or recombinant anti-human ICOS Ab, with or without a signal peptide, can be expressed as recombinant Abs using plasmids (or any expression vehicle) encoding the respective heavy and light chains, or the heavy and light chains can be encoded in separate expression vehicles.

[0031] In some embodiments, the heavy and light chains can be expressed (in cis or trans) from the pTT5™ vector (National Research Council of Canada, NRC-CNRC, Canada) in HEK293-6E cells. In alternative embodiments, the vector or vectors expressing the heavy and / or light chains are episomal or chromosomally integrated, e.g., in a stable cell line capable of synthesizing, optionally inducibly synthesizing, the heavy and / or light chains.

[0032] In alternative embodiments, nucleic acids encoding the chimeric or recombinant Abs provided herein are provided. The nucleic acids provided herein can be produced, isolated, and / or manipulated, for example, by cloning and expressing cDNA libraries, amplifying message or genomic DNA by PCR, etc. Nucleic acids used to practice the embodiments provided herein can be isolated, genetically engineered, amplified, and / or recombinantly expressed / produced from a variety of sources, whether RNA, cDNA, genomic DNA, vectors, viruses, or hybrids thereof. Recombinant polypeptides produced from these nucleic acids can be individually isolated or cloned and tested for the desired activity. Any recombinant expression system can be used, including bacterial, fungal, mammalian, yeast, insect, or plant cell expression systems.

[0033] Alternatively, these nucleic acids can be synthesized in vitro by well-known chemical synthesis techniques, for example, as described in Adams (1983) J. Am. Chem. Soc. 105:661; Belousov (1997) Nucleic Acids Res. 25:3440-3444; Frenkel (1995) Free Radic. Biol. Med. 19:373-380; Blommers (1994) Biochemistry 33:7886-7896; Narang (1979) Meth. Enzymol. 68:90; Brown (1979) Meth. Enzymol. 68:109; Beaucage (1981) Tetra. Lett. 22:1859; U.S. Pat. No. 4,458,066.

[0034] Techniques for the manipulation of nucleic acids, such as subcloning, probe labeling (e.g., random primer labeling using Klenow polymerase, nick translation, amplification), sequencing, hybridization, etc., are well described in the scientific and patent literature; see, e.g., Sambrook, ed., MOLECULAR CLONING: A LABORATORY MANUAL (2ND ED.), Vols. 1-3, Cold Spring Harbor Laboratory, (1989); CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, Ausubel, ed. John Wiley & Sons, Inc., New York (1997); LABORATORY TECHNIQUES IN BIOCHEMISTRY AND MOLECULAR BIOLOGY: HYBRIDIZATION WITH NUCLEIC ACID PROBES, Part I. Theory and Nucleic Acid Preparation, Tijssen, ed. Elsevier, NY (1993).

[0035] Another useful means for obtaining and manipulating the nucleic acid used to carry out the embodiments provided herein includes, for example, screening and recloning the insert that is isolated or amplified from genomic clone or cDNA clone.The source of nucleic acid includes, for example, mammalian artificial chromosome (MAC), for example, see U.S. Patent No. 5,721,118; U.S. Patent No. 6,025,155; human artificial chromosome, for example, see Rosenfeld (1997) Nat.Genet.15:333-335; yeast artificial chromosome (YAC); bacterial artificial chromosome (BAC); P1 artificial chromosome, for example, see Woon (1998) Genomics 50:306-316; P1-derived vector (PAC), for example, see Kern (1997) Biotechniques 23:120-124; recombinant nucleic acid sequence, genome or cDNA library, contained in and / or expressed in cosmid, recombinant virus, phage, phagemid or plasmid.

[0036] In alternative embodiments, the nucleic acids provided herein are operably linked to a transcriptional regulatory element, including a promoter, which can be a constitutive or inducible transcriptional regulatory element.

[0037] In an alternative aspect, "expression cassettes" are provided that include a nucleotide sequence provided herein, e.g., encoding a chimeric or recombinant antibody provided herein. Expression cassettes can include at least a transcriptional regulatory element, e.g., a promoter, operably linked to the antibody coding sequence, and can optionally also include a transcription termination signal. Additional factors that are necessary or helpful in effecting expression can also be used, e.g., enhancers.

[0038] In alternative aspects, expression cassettes used to practice the embodiments provided herein include plasmids, expression vectors, recombinant viruses, any form of recombinant "naked DNA" vector, and the like. In alternative aspects, "vectors" used to practice the embodiments provided herein can comprise nucleic acids capable of infecting, transfecting, transiently, or permanently transducing cells. In alternative aspects, vectors used to practice the embodiments provided herein can be naked nucleic acids or nucleic acids complexed with proteins or lipids. In alternative aspects, vectors used to practice the embodiments provided herein can comprise viral or bacterial nucleic acids and / or proteins, and / or membranes (e.g., cell membranes, viral lipid envelopes, etc.). In alternative aspects, vectors used to practice the embodiments provided herein include, but are not limited to, replicons (e.g., RNA replicons, bacteriophages) to which fragments of DNA can be ligated and replicated. Thus, vectors include, but are not limited to, RNA, autonomously self-replicating circular or linear DNA or RNA (e.g., plasmids, viruses, etc., see, e.g., U.S. Pat. No. 5,217,879), and can include both expression and non-expression plasmids. In alternative aspects, vectors used to practice the embodiments provided herein can be stably replicated by cells during mitosis as autonomous structures, or can be integrated into the host genome.

[0039] In alternative aspects, a "promoter" used to practice the embodiments provided herein includes any sequence capable of driving transcription of a coding sequence in a cell, such as a bacterial, yeast, fungal, plant, insect (e.g., baculovirus), or mammalian cell. Thus, promoters used in the constructs include cis-acting transcriptional control elements and regulatory sequences involved in regulating or altering the timing and / or rate of transcription of a gene. For example, a promoter used to practice the embodiments provided herein can be a cis-acting transcriptional control element, including an enhancer, promoter, transcription terminator, origin of replication, chromosomal integration sequence, 5' and 3' untranslated region, or intronic sequence, involved in transcriptional regulation. These cis-acting sequences can interact with proteins or other biomolecules to effect (turn on / off, regulate, alter, etc.) transcription.

[0040] A "constitutive" promoter used to practice the embodiments provided herein may be one that continuously drives expression under most environmental conditions and states of development or cell differentiation. An "inducible" or "regulatable" promoter used to practice the embodiments provided herein is capable of directing expression of a nucleic acid provided herein under the influence of an environmental or developmental condition. An example of an environmental condition that may affect transcription by an inducible promoter used to practice the embodiments provided herein includes the presence of an inducer administered to a cell.

[0041] In an alternative embodiment, a nucleic acid used to practice the embodiments provided herein encodes a polypeptide having the following amino acid sequence:

[0042] Summary of Exemplary Polypeptide Sequences (SEQ ID NO: 1) IgG heavy chain variable domain (SEQ ID NO: 2) Variable domain of Kappa 1 light chain (SEQ ID NO: 3) Heavy chain constant region: (SEQ ID NO: 4) Heavy chain variable and constant region: (SEQ ID NO: 5) Heavy chain variable region amino acid terminal signal sequence (SEQ ID NO: 6) Heavy chain variable region with signal sequence (SEQ ID NO: 7) Heavy chain including variable and constant domains with amino-terminal signal sequence (SEQ ID NO: 8) Light chain constant region (SEQ ID NO: 9) Light chain including variable and constant regions (SEQ ID NO: 10) Light chain variable domain amino-terminal signal sequence (SEQ ID NO: 11) Light chain variable domain with signal sequence (SEQ ID NO: 12) Light chain with signal sequence

[0043] Exemplary Polypeptide Sequences SEQ ID NO: 1 (variable domain of IgG heavy chain) QSLEESGGRLVTPGTPLTLTCTVS GFSLSSYG VSWVRQAPGKGLEWIGI INSDHST YYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFC ARSYGIGSIF WGPGTLVTVSS SEQ ID NO: 2 (variable domain of Kappa 1 light chain) AAVLTQTPSPVSAAVGGTVSISCQSS KSVYNNNQ LSWFQQKPGQRPKLLIY EAF KLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYC AAVYSDDSDNS FGGGTEVVVK (SEQ ID NO: 3) Heavy chain constant region: GQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVR TARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 4) Heavy chain variable and constant region: QSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLV TVSSGQPKAPSVFPLAPCCGDTPSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTC PPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISK ARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 5) Heavy chain variable region amino acid terminal signal sequence METGLRWLLLVAVLKGVQC (SEQ ID NO: 6) Heavy chain variable region with signal sequence METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLVTVSS a heavy chain containing variable and constant domains with an amino-terminal signal sequence (SEQ ID NO: 7) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCAR SYGIGSIFWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTV APSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALAPIE KTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK Light chain constant region: (SEQ ID NO: 8) GDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC Light chains containing variable and constant regions: (SEQ ID NO: 9) AAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTE VVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 10) Light chain variable domain amino-terminal signal sequence MDTRAPTQLLGLLLLWLPGATF (SEQ ID NO: 11) A light chain variable domain with a signal sequence MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVK Includes. (SEQ ID NO: 12) The light chain with the signal sequence MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSD DSDNSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC Includes.

[0044] <Peptides, Polypeptides, Peptidomimetics> In alternative embodiments, peptides and polypeptides used to practice the embodiments provided herein can include any "mimetics" and / or "peptidomimetics" forms. In alternative embodiments, peptides and polypeptides used to practice the embodiments provided herein can include synthetic compounds having substantially the same structural and / or functional characteristics of natural polypeptides, such as the chimeric or recombinant antibodies provided herein. Mimetics used to practice the embodiments provided herein can be either entirely composed of synthetic, non-natural analogs of amino acids or chimeric molecules of partly natural peptide amino acids and partly non-natural analogs of amino acids. Mimetics can also incorporate any amount of natural amino acid conservative substitutions, so long as such substitutions also do not alter the structure and / or activity of the mimetic. Routine experimentation will determine whether a mimetic is effective for practicing the invention, e.g., whether a mimetic composition is effective in specifically binding to ICOS protein. The methodologies detailed herein and others known to those skilled in the art can be used to select or guide the selection of mimetics effective for practicing the compositions and / or methods of the invention.

[0045] Polypeptide mimetic compositions for practicing the embodiments provided herein can include any combination of non-natural structural components. In alternative aspects, mimetic compositions for practicing the embodiments provided herein can include one or all of three types of structural groups: a) residue linking groups other than natural amide bond ("peptide bond") linkages; b) non-natural residues in place of naturally occurring amino acid residues; or c) residues that induce secondary structure mimicry, i.e., induce or stabilize secondary structure, such as β-turn, γ-turn, β-sheet, α-helical conformation, etc. For example, a polypeptide can be characterized as a mimetic if all or some of its residues are linked by chemical means other than natural peptide bonds. In alternative aspects, mimetic compositions for practicing the embodiments provided herein can be peptoids, in which side chains are linked to the nitrogen of the peptide backbone rather than the α-carbon as in peptides; and peptoids lack the amide hydrogens that are involved in many of the secondary structural elements in peptides and proteins. In an alternative aspect, the mimetic compositions for practicing the embodiments provided herein can be beta peptides (β-peptides) in which the amino group is linked to the β carbon (i.e., two carbon atoms away from the carboxylic acid group).

[0046] In alternative embodiments, peptides and polypeptides used to practice the embodiments provided herein can be suitably deuterated, e.g., hydrogen is replaced with deuterium ("-D") at a specific position, with the understanding that the abundance of deuterium at that position is greater than or substantially greater than 0.015%, the natural abundance of deuterium. For example, in alternative embodiments, deuterium substitution, or "enrichment," occurs at a specific position or multiple specific positions. In one embodiment, the deuterium enrichment is about 1% or greater, or the deuterium enrichment is about 1%, 5%, 10%, 20%, 50%, 70%, 80%, or 90% or greater, or is between about 1% and 99%.

[0047] <Examples of immunohistochemistry (IHC) techniques and equipment>In alternative embodiments, the immunohistochemistry (IHC) methodology and / or reagents used to practice the compositions, products, kits, or methods provided herein are described, for example, in U.S. Pat. No. 11,321,881 (describing IHC imaging protocols and apparatus); U.S. Pat. No. 11,249,085 (describing the application of click chemistry for signal amplification in IHC and ISH assays); U.S. Pat. No. 11,222,424 (describing IHC imaging apparatus and computer programs); or methods using multi-dye quinone methide and tyramide conjugates. No. 11,143,648, which describes novel colors for chromogenic IHC and ISH staining; No. 11,047,774, which describes an automated IHC specimen processing system; No. 11,028,044, which describes a process for commercial-scale preparation of 3,3'5,5'-tetramethylbenzidine (TMB) and its salts; No. 10,977,791, which describes a computer-implemented method for analysis of tissue samples; No. 10,948,493, which describes an IHC method; No. 10,937,162, which describes an IHC image analysis algorithm; and No. 10,937,162, which describes an IHC image analysis algorithm; and microscope slides. No. 10,816,443, which describes an automated batch staining machine for staining the above biological specimens; No. 10,718,773, which describes a method for determining the eligibility of a subject with a malignant tumor for treatment with a therapeutic agent; No. 10,565,479, which describes a method for identifying blurred areas in a digital image of stained tissue; No. 10,564,076, which describes a system for preparing samples for analysis (or IHC); No. 10,551,395, which describes an automated histological staining system; No. 10,551,378, which describes a tissue staining system. No. 10,504,224 (describes a digital tissue image analysis system for IHC); No. 10,501,777 (describes simultaneous multiplexed detection and quantification of protein expression in IHC); No. 10,488,340 (describes a method for extracting images of target fluorophores in biological material); No. 10,453,195 (describes a method for detecting tissue regions of interest using digital pathology imaging); No. 10,438,381 (describes devices, systems and methods for generating digital images of tissue sections);No. 10,416,176 (describes a method for processing specimens in an automated histological staining system); No. 10,393,633 (describes a method for processing IHC samples and preventing deterioration); No. 10,217,011 (describes handling of IHC slides); No. 10,209,165 (describes an automated or semi-automated method for assessing the quality of staining of cell-containing specimens); No. 10,126,216 (describes a method for fixing tissue samples for IHC); No. 9,423,322 (describes a method for fixing tissue samples for IHC); No. 9,103,822, which describes polymeric carriers for chemistry and in situ hybridization; No. 8,515,683, which describes methods and systems for automated detection of immunohistochemistry (IHC) patterns; No. 10,816,443, which describes an automated batch stainer for staining biological specimens or microscope slides; or U.S. Patent Application Publication No. 2021 / 023, which describes compositions for forming porous hydrogels around cells suitable for immunostaining of cells within the hydrogel. 9683 A1; or U.S. Patent No. 11,112,413, or U.S. Patent Application Publication No. 2022 / 0057408 A1, which describes methods of using epitope-tagged antibodies to detect one or more targets in IHC tissue samples; or U.S. Patent Application Publication No. 2021 / 0048432 A1, which describes direct immunohistochemistry (IHC) staining and direct immunocytochemistry (ICC) techniques; or U.S. Patent Application Publication No. 2020 / 0292536, which describes synthetic controls useful in immunohistochemistry (IHC) assays ... No. 2022 / 0057408 A1, which describes the use of antibodies with epitope tags in (IHC) assays; or No. 2021 / 0201485 A1, which describes a computer-implemented method for the analysis of tissue samples; No. 2019 / 0178867 A1 (which describes the detection of specific tissue objects within thin sections of tissue samples when imaged in a bright-field microscope without the use of chromogenic stains specific for the tissue objects); No. 2019 / 0156510 A1 (which describes an image analysis method for analyzing IHC tissue samples);No. 2019 / 0293637 A1 (methods and systems for quantitative immunohistochemistry (IHC) of target protein molecules); No. 2019 / 0080450 A1 (describing automated determination of staining quality of IHC-stained biological samples); or No. 2020 / 0316589 A1 (describing multi-well solid support containers for processing and testing fixed biological material); or methods or for producing rapid immunohistochemical detection of antigens from biological samples. The method may include or involve the use of any IHC protocol, IHC equipment, device for performing IHC and / or image or data analysis system or IHC reagent known in the art, as described in US Patent No. 2022 / 0229062 A1, which describes immunohistochemistry (IHC) for producing cells; US Patent No. 2021 / 0371520 A1, which describes various immunohistochemical (IHC) methodologies; or US Patent No. 2022 / 0034766 A1, which describes immunohistochemical staining techniques for identifying cells;

[0048] In alternative embodiments, the chimeric or recombinant antibodies, antigen-binding fragments thereof, or monomeric or dimeric antigen-binding proteins in the IHC protocols or kits provided herein are substantially purified or isolated, or are in the form of crude or partially purified culture supernatants.

[0049] In alternative embodiments, the methods provided herein can use or include any products or methods known in the art and reagents for detecting or visualizing antibody-antigen interactions using, for example, IHC protocols or reagents.

[0050] In an alternative embodiment, the methods provided herein include the use of chromogenic immunohistochemistry (CIH), in which a primary antibody (e.g., a chimeric or recombinant antibody (Ab), or antigen-binding fragment thereof, or monomeric or dimeric antigen-binding protein provided herein) or a secondary antibody (e.g., a secondary antibody that binds to a chimeric or recombinant antibody (Ab), or antigen-binding fragment thereof, or monomeric or dimeric antigen-binding protein provided herein after it specifically binds, pairs with, or associates with an ICOS epitope or polypeptide) is conjugated to an enzyme, such as a peroxidase (or immunoperoxidase), e.g., horseradish peroxidase (HRP), that can catalyze a color-developing reaction.

[0051] In alternative embodiments, the methods provided herein include the use of immunofluorescence, in which a primary or secondary antibody is tagged with a fluorophore, such as fluorescein or fluorescein isothiocyanate (FITC), triarylmethane dyes, e.g., rhodamine or rhodamine derivatives (e.g., tetramethylrhodamine (TRITC), rhodamine 6G, rhodamine 123, rhodamine B, carboxytetramethylrhodamine (TAMRA), tetramethylrhodamine (TMR), sulforhodamine 101), aminomethylcoumarin acetate (AMCA), ALEXA™, or DYLIGHT™ fluor. 3,3'-Diaminobenzidine (DAB) can also be used.

[0052] In alternative embodiments, the methods provided herein involve the use of a direct or one-step staining method, in which a primary antibody (e.g., a chimeric or recombinant antibody (Ab) provided herein, or an antigen-binding fragment thereof, or a monomeric or dimeric antigen-binding protein) is labeled and reacts directly with an antigen, e.g., in a tissue section. This technique utilizes only one antibody and is therefore simple and rapid, but may have relatively low sensitivity due to little signal amplification.

[0053] In an alternative embodiment, the methods provided herein include the use of an indirect method, in which an unlabeled primary antibody (first layer) binds to a target antigen (e.g., TTF-1), for example, in a tissue or organ, followed by reacting a labeled secondary antibody (second layer) with the primary antibody. The secondary antibody can be directed against the isotype of the animal species from which the primary antibody is derived, e.g., IgG. This method can be more sensitive than direct detection strategies when the secondary antibodies are conjugated to a detection agent such as a fluorescent or enzyme reporter, due to signal amplification resulting from the binding of several secondary antibodies to each primary antibody.

[0054] In an alternative embodiment, further amplification is achieved when the secondary antibody is conjugated to several detection molecules, for example, a biotin molecule that can recruit a complex of avidin, streptavidin, or NEUTRAVIDIN™ protein-linked enzyme.

[0055] In alternative embodiments, IHC is performed on tissue sections or tissue biopsies, e.g., paraformaldehyde (PFA)-fixed tissues or organs, or formalin-fixed, paraffin-embedded tissues. In alternative embodiments, tissues are sectioned or used whole. Prior to sectioning, tissue samples can be embedded in a medium, e.g., paraffin wax or freezing medium. Tissue sections can be sectioned on a variety of instruments, most commonly using a microtome, cryostat, or vibratome. Specimens can be sectioned at thicknesses ranging from approximately 3 μm to 5 μm. Sections can be mounted on slides, dehydrated using alcohol washes of increasing concentrations (e.g., 50%, 75%, 90%, 95%, 100%), and cleared using a detergent such as xylene, before being imaged under a microscope.

[0056] Depending on the method of fixation and tissue preservation, samples may require additional steps to make ICOS epitopes available for antibody binding, including deparaffinization and antigen retrieval. For formalin-fixed, paraffin-embedded tissue, antigen retrieval is often necessary and can involve pre-treating sections with heat or proteases.

[0057] In an alternative embodiment, IHC is performed using the ENVISION DUOFLEX DOUBLESTAIN SYSTEM™ (Agilent, San Jose, CA), which allows for staining of two or more markers on a single slide. In an alternative embodiment, IHC is performed using the EnVision FLEX HRP Magenta High pH (DAKO OMNIS™, Agilent, San Jose, CA) system, and binding can be visualized with the EnVision FLEX HRP™ magenta chromogen. In an alternative embodiment, IHC is performed using the EnVision FLEX Mini Kit™ High pH, ​​a highly sensitive visualization system intended for use in IHC in conjunction with a DAKO AUTOSTAINER™ instrument; this dual-link system detects primary mouse and rabbit antibodies, and the reaction is visualized with 3,3'-diaminobenzidine (DAB) chromogen (DAB forms a water-insoluble brown precipitate when oxidized, for example, by peroxidase).

[0058] <Products and Kits> For example, articles of manufacture and kits are provided for practicing the methods provided herein that include chimeric or recombinant anti-ICOS binding proteins, such as the anti-ICOS polypeptide Abs provided herein; and optionally, the articles of manufacture and kits can further include some or all of the reagents needed to perform IHC, and optionally, include instructions for practicing the methods provided herein.

[0059] In an alternative embodiment, the article of manufacture or kit comprises a mixture or cocktail of antibodies (Abs) provided herein, e.g., a mixture or cocktail comprising two, three or more anti-human ICOS binding proteins, such as anti-ICOS antibodies (Abs).

[0060] In an alternative embodiment, the article of manufacture, or kit, comprises a mixture or cocktail of antibodies (Abs) comprising antibodies comprising the heavy and / or light chain CDRs of the antibodies provided herein or as produced by the antibody-producing clones provided herein.

[0061] In an alternative embodiment, the article of manufacture, or kit, comprises an antibody-producing clone provided herein.

[0062] Any of the above aspects and embodiments may be combined with any other aspect or embodiment as disclosed herein in the Summary, Drawings and / or Detailed Description sections.

[0063] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0064] Unless specifically stated otherwise or apparent from context, as used herein, the term "or" is understood to be inclusive, covering both "or" and "and."

[0065] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to be within the normal tolerance in the art, for example, within 2 standard deviations of the mean. About (use of the term "about") can be understood to be within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0066] Unless specifically stated or apparent from context, as used herein, the terms "substantially all," "substantially a majority of," "substantially all of," or "the majority of" encompass at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% or more of the referenced amount of a composition.

[0067] Each patent, patent application, publication, and document referenced herein is incorporated herein by reference in its entirety. Citation of the above patents, patent applications, publications, and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. The incorporation by reference of these documents should not be construed as an assertion or admission that any portion of the contents of any document is deemed essential material for satisfying any national or territorial statutory disclosure requirements for patent applications. Nevertheless, the right is reserved, in appropriate cases, to rely on any of such documents to provide material deemed essential to claimed subject matter by an examining authority or court.

[0068] Modifications to the foregoing can be made without departing from the basic aspects of the invention. While the present invention has been described in considerable detail with reference to one or more specific embodiments, those skilled in the art will understand that modifications can be made to the embodiments specifically disclosed in this application, and that these modifications and improvements fall within the scope and spirit of the invention. The invention illustratively described herein can be practiced in the absence of any element not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" can be replaced with either of the other two terms. Accordingly, the terms and expressions employed are used as terms of description and not of limitation, and do not exclude equivalents of the features shown and described, or portions thereof, recognizing that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.

[0069] The present invention will be further illustrated with reference to the examples described herein; however, it should be understood that the invention is not limited to such embodiments. [Example]

[0070] Unless otherwise specified in the examples, all recombinant DNA techniques are performed according to standard protocols, for example as described in Sambrook et al. (2012) Molecular Cloning: A Laboratory Manual, 4th Edition, Cold Spring Harbor Laboratory Press, NY and Ausubel et al. (1994) Current Protocols in Molecular Biology, Current Protocols, USA, Volumes 1 and 2. Other references for standard molecular biology techniques include Sambrook and Russell (2001) Molecular Cloning: A Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, NY, and Brown (1998) Molecular Biology LabFax, Second Edition, Academic Press (UK), Volumes I and II. Standard materials and methods for the polymerase chain reaction can be found in Dieffenbach and Dveksler (1995) PCR Primer: A Laboratory Manual, Cold Spring Harbor Laboratory Press, and McPherson at al. (2000) PCR-Basics: From Background to Bench, First Edition, Springer Verlag, Germany.

[0071] Example 1: Generation of exemplary Abs The ICOS antigen was designed using a portion of the intracellular domain of human ICOS. The antigen was generated as a synthetic peptide. This antigen was used to immunize rabbits, and blood samples were subsequently collected to confirm seroreactivity to human ICOS by ELISA and IHC.

[0072] Rabbits showing the best immune response to human ICOS when tested against multiple ICOS-positive human tissues and different non-expressing tissues were selected for B cell selection using blood samples from immunized rabbits.

[0073] Briefly, B cells expressing antibodies that bind to the immunogen were isolated and cultured as monoclonals and then tested for ICOS specificity in ELISA. ELISA-specific clones were further tested in ultrasensitive IHC against normal and clinical tissues using a high-pH antigen retrieval buffer. The best-performing clones were selected based on IHC performance. The antibody variable domains were cloned into custom-made expression vectors based on the pTT5™ (National Research Council of Canada, NRC-CNRC, Canada) backbone, containing the constant domains of the heavy and κ1 light chains, respectively. The recombinant antibodies were expressed in HEK293-6E cells.

[0074] The recombinant antibodies were tested for human ICOS binding by BioLayer Interferometry (BLI) on BLItz and then in IHC by standard FLEX protocols on normal and clinical tissues.

[0075] Some antibodies were identified that showed ICOS-specific staining in IHC. Clone 1E9 / 4B7 showed very promising results on the tissues tested. Antibodies were tested for specificity on different clinical tissues, demonstrating their utility for in vitro diagnostics by immunohistochemistry.

[0076] 1A-D illustrate images of IHC staining of tonsil cells (FIG. 1A), melanoma cells (FIG. 1B), liver cells (FIG. 1C), and colon cells (FIG. 1D) comparing an exemplary anti-human ICOS antibody (Ab) provided herein, also designated T0251A, having a heavy chain with an amino acid sequence comprising SEQ ID NO:4; and a light chain with an amino acid sequence comprising SEQ ID NO:9, with a reference anti-human ICOS Ab (Abscam, designated SP98). DAKO OMNIS™ (Agilent, San Jose, CA) staining IHC protocol was used for IHC staining of both T0251A and SP98. T0251A was used at 0.5 μg / mL and SP98 was used at a 1 / 50 dilution; both T0251A and SP98 IHC used TARGET RETRIEVAL SOLUTION™ (TRS) (Agilent, San Jose, Calif.) high pH with rabbit linker.

[0077] Although a number of embodiments of the present invention have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. An isolated or purified antibody (Ab), or an antigen (Ag)-binding fragment thereof, or a monomeric or dimeric antigen-binding protein (ABP), capable of specifically binding to human ICOS (inducible T-cell costimulatory molecule) protein or human CD278 polypeptide, (a) the following sequence: (1) an amino acid sequence comprising the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO: 1, or CDR1 amino acid (aa) residues GFSLSSYG (residues 25-32 of SEQ ID NO: 1), CDR2 aa residues INSDHST (residues 50-56 of SEQ ID NO: 1), and CDR3 aa residues ARSYGIGSIF (residues 93-102 of SEQ ID NO: 1); or (2) an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98% sequence identity, or about 70% to 100% sequence identity, to each of the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO: 1, or to CDR1 amino acid (aa) residues GFSLSSYG (residues 25-32 of SEQ ID NO: 1), CDR2 aa residues INSDHST (residues 50-56 of SEQ ID NO: 1), and CDR3 aa residues ARSYGIGSIF (residues 93-102 of SEQ ID NO: 1), or (3) An amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, or 98% sequence identity to SEQ ID NO: 1, or about 70% to 100% sequence identity, or an amino acid sequence having complete sequence identity to SEQ ID NO:

1. a heavy chain variable region (VH) comprising: (b) the following sequence: (1) an amino acid sequence comprising the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO:2, or CDR1 amino acid (aa) residues KSVYNNNQ (residues 27-34 of SEQ ID NO:2), CDR2 aa residues EAF (residues 52-54 of SEQ ID NO:2), and CDR3 aa residues AAVYSDDSDNS (residues 91-101 of SEQ ID NO:2); or (2) an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98% sequence identity, or about 70% to 100% sequence identity, to each of the three CDR1, CDR2, and CDR3 complementarity determining regions (CDRs) of SEQ ID NO:2, or to CDR1 amino acid (aa) residues KSVYNNNQ (residues 27-34 of SEQ ID NO:2), CDR2 aa residues EAF (residues 52-54 of SEQ ID NO:2), and CDR3 aa residues AAVYSDDSDNS (residues 91-101 of SEQ ID NO:2), or (3) An amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, or 98% sequence identity to SEQ ID NO: 2, or about 70% to 100% sequence identity, or an amino acid sequence having complete (100%) sequence identity to SEQ ID NO:

2. a light chain variable region (VL) comprising: (c) the heavy chain variable region (VH) of (a) and the light chain variable region (VL) of (b) 1. An isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, comprising:

2. antigen-binding fragments (Fab, or Ab fragments having only one constant domain and one variable domain of each of the Ab heavy and light chains); F(ab') ２ (or digested with pepsin to give F(ab') ２ an Ab that produces two fragments: a pFc' (pepsin-cleavable Fc) fragment and a pFc' (pepsin-cleavable Fc) fragment; Fab' (F(ab') ２ single stranded fragments), single-chain variable fragments (scFv) (or fusion proteins of the variable regions of the Ab heavy and light chains, optionally linked together using a linker peptide of about 10 to about 25 amino acids in length); (scFv) ２ or a di-scFv or a bi-scFv, or a single peptide chain with two variable heavy chain regions and two variable light chain regions resulting in a tandem scFv; minibodies (or fusion proteins of Ab heavy and light chain variable regions linked together using alkyl groups, optionally methyl or ethyl groups); diabodies (or scFvs with a linker peptide that is too short (optionally about 5 amino acids) for the two variable regions to fold together, thereby forcing the scFv to dimerize), triabodies or tetrabodies (or scFvs with a linker peptide that is too short (optionally about 5 amino acids) for the two variable regions to fold together, thereby forcing the scFv to trimerize or tetramerize), single domain antibodies (dABs) (or single variable regions of Ab heavy or Ab light chains); a plurality of complementarity determining region (CDR) fragments, or Multispecific antibodies formed from two or more antibody fragments 2. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 1, produced as or in the form of:

3. the heavy chain variable region (VH), when present, Amino acid sequence: QSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLVTVSS (SEQ ID NO: 1), or comprising SEQ ID NO: 1 with one or more amino acid substitutions, additions (insertions) or deletions, and wherein said recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP retains its ability to specifically bind to a human ICOS protein or polypeptide.

3. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 1 or 2.

4. 4. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 3, wherein the one or more amino acid substitutions in the heavy chain variable region (VH) comprise one or more conservative amino acid substitutions.

5. 5. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 4, wherein the one or more conservative amino acid substitutions comprise substitution of an aliphatic amino acid with another aliphatic amino acid; substitution of serine with threonine or vice versa; substitution of an acidic residue with another acidic residue; substitution of a residue bearing an amide group with another residue bearing an amide group; exchange of a basic residue with another basic residue; or substitution of an aromatic residue with another aromatic residue.

6. 6. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 5, or any one of the preceding claims, wherein the heavy chain variable region further comprises at least a portion of a heavy chain constant region.

7. the heavy chain constant region having the amino acid sequence: GQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 3) 7. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 6, comprising:

8. The heavy chain has the sequence: QSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLVT VSSGQPKAPSVFPLAPCCGDTPSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPP ELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 4) 8. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 7, comprising a heavy chain variable region and a heavy chain constant region comprising:

9. 8. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 7, or any one of the preceding claims, wherein the heavy chain variable region comprises an amino acid-terminal signal sequence.

10. 10. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 9, or of any one of the preceding claims, wherein the heavy chain variable region amino acid terminal signal sequence comprises the sequence METGLRWLLLVAVLKGVQC (SEQ ID NO: 5).

11. The heavy chain variable region having a signal sequence is METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSYGIGSIFWGPGTLVTVSS (SEQ ID NO: 6), or The heavy chain comprising variable and constant domains and having a signal sequence has the sequence: METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSSYGVSWVRQAPGKGLEWIGIINSDHSTYYAKWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSY GIGSIFWGPGTLVTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPST CSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 7) 11. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 10, or of any one of the preceding claims, comprising:

12. the light chain variable region (VL), when present, (a) amino acid sequence: AAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVK (SEQ ID NO: 2), or 2 having one or more amino acid substitutions, additions (insertions) or deletions, and wherein said recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP retains its ability to specifically bind to a human ICOS protein or polypeptide.

12. An isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP according to any one of claims 1 to 11, or according to any one of the preceding claims.

13. 13. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 12, wherein the one or more amino acid substitutions in the light chain variable region (VL) comprise one or more conservative amino acid substitutions.

14. 14. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 13, wherein the one or more conservative amino acid substitutions comprise conservative substitutions including substitution of an aliphatic amino acid with another aliphatic amino acid; substitution of serine with threonine or vice versa; substitution of an acidic residue with another acidic residue; substitution of a residue bearing an amide group with another residue bearing an amide group; exchange of a basic residue with another basic residue; or substitution of an aromatic residue with another aromatic residue.

15. 10. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 9, or any one of the preceding claims, wherein the light chain variable region further comprises at least a portion of a light chain constant region.

16. the light chain constant region having the amino acid sequence: GDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 8) 16. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 15, comprising:

17. the light chain has the sequence: AAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 9) 17. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 16, comprising a variable region and a constant region comprising:

18. 18. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 17, or any one of the preceding claims, wherein the light chain variable domain further comprises an amino-terminal signal sequence.

19. the amino-terminal signal sequence of the light chain variable domain is MDTRAPTQLLGLLLLWLPGATF (SEQ ID NO: 10) 20. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 18, comprising:

20. the light chain variable domain having a signal sequence, MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVK (SEQ ID NO: 11), or the light chain having a signal sequence, MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSKSVYNNNQLSWFQQKPGQRPKLLIYEAFKLPSGVPSRFKGSGSGTQFTLTISDVQCDDAATYYCAAVYSDDSDNSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC (SEQ ID NO: 12) 20. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 19, comprising:

21. 21. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 20, or of any one of the preceding claims, wherein SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, and / or SEQ ID NO:12 have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 conservative amino acid substitutions, and the recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP retains its ability to specifically bind to a human ICOS protein or polypeptide.

22. 22. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 21, or any one of the preceding claims, wherein the heavy chain constant region comprises an amino acid sequence derived from an IgG, IgM, IgA, IgD, or IgE isotype.

23. 24. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 23, or any one of the preceding claims, wherein the light chain constant region comprises an amino acid sequence derived from a kappa (κ) or lambda (λ) isotype.

24. 24. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 23, or of any one of the preceding claims, wherein at least a portion of the heavy chain constant region, at least a portion of the light chain constant region, or at least a portion of the heavy chain constant region and the light chain constant region is or comprises an amino acid sequence of human, rabbit, mouse or rat origin, or comprises a constant region amino acid sequence derived from human, rabbit, mouse or rat.

25. 25. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 24, or of any preceding claim, wherein at least a portion of the heavy chain constant region, at least a portion of the light chain constant region, or at least a portion of the heavy chain constant region and the light chain constant region is or comprises a synthetic amino acid sequence.

26. 26. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 25, or of any one of the preceding claims, wherein the recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, or the heavy chain constant region, or the light chain constant region, or the heavy chain constant region and the light chain constant region, further comprises or is bound to a heterologous protein, peptide, or compound or composition.

27. 27. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 26, wherein the heterologous protein or peptide, or the compound or composition comprises a detectable protein, detectable agent, or binding moiety.

28. 27. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 26, wherein the heterologous protein or peptide comprises a carrier protein.

29. 29. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, of any one of claims 26 to 28, wherein the heterologous protein, peptide, or compound or composition is covalently conjugated to the recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP.

30. 30. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 26-29, wherein the detectable agent or binding moiety comprises biotin, a fluorescent or chemiluminescent label, a fluorophore, perylene, fluorenyl, coumarin, 7-methoxycoumarin (Mca), 4-(dimethylaminoazo)benzene-4-carboxylic acid (dabcyl), Tamra, boron-dipyrromethene (BODIPY), or derivatives thereof, a dye, a radioisotope, a quantum dot or photoluminescent aqueous nanocrystal, a hapten, or an antibody-binding epitope or domain.

31. 32. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 31, wherein the dye is or comprises rhodamine, [2-(4-nitro-2,1,3-benzoxadiazol-7-yl)aminoethyl]trimethylammonium (NBD), Nile red, or Nile blue, or is a sulfoindocyanine-containing fluorescent dye.

32. 32. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 31 , wherein the fluorophore is or comprises a dansyl, fluorescein, carboxyfluorescein (FAM), or 6-FAM moiety.

33. 32. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 31, wherein the dye is or comprises a cyanine dye, Cy3 or Cy5.

34. 32. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of claim 31, wherein the hapten is or comprises a biotin, theophylline, digoxigenin, carborane, fluorescein, or bromodeoxyuridine moiety.

35. 36. The isolated or purified Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 35, or of any one of the preceding claims, which is a recombinant Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, or comprises a peptide or polypeptide produced by recombinant technology.

36. 36. A chimeric or recombinant nucleic acid comprising a nucleic acid sequence encoding the Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP of any one of claims 1 to 35.

37. 37. The chimeric or recombinant nucleic acid of claim 36, further comprising and operably linked to a transcriptional regulatory element.

38. 38. The chimeric or recombinant nucleic acid of claim 37, wherein the transcriptional regulatory element comprises a promoter.

39. 39. The chimeric or recombinant nucleic acid of claim 38, wherein the promoter is an inducible promoter or a constitutive promoter.

40. 40. The chimeric or recombinant nucleic acid of any one of claims 36 to 39, further comprising a sequence encoding an amino-terminal signal peptide.

41. The amino-terminal signal peptide has the amino acid sequence: METGLRWLLLVAVLKGVQC (SEQ ID NO: 5); or MDTRAPTQLLGLLLLWLPGATF (SEQ ID NO: 10) 41. The chimeric or recombinant nucleic acid of claim 40, comprising:

42. 42. An expression cassette, vector, recombinant virus, artificial chromosome, cosmid or plasmid which comprises or has contained therein a chimeric or recombinant nucleic acid according to any one of claims 36 to 41.

43. 42. A cell comprising or having contained therein a chimeric or recombinant antibody or dimeric antigen binding protein of any one of claims 1 to 35, a chimeric or recombinant nucleic acid of any one of claims 36 to 41, or an expression cassette, vector, recombinant virus, artificial chromosome, cosmid or plasmid of claim 42.

44. 44. The cell of claim 43, wherein the cell is a bacterial, fungal, mammalian, yeast, insect or plant cell.

45. 45. The cell of claim 44, wherein the mammalian cell is a human cell.

46. (a) contacting a cell, tissue or organ, or a portion of any of the above, with at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP according to any one of claims 1 to 35, or any one of the preceding claims; and (b) detecting specific binding of at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP, to a BCMA polypeptide within or on the surface of a cell, tissue, or organ, or a portion of any of the foregoing; thereby detecting the presence of human BCMA protein within or on the surface of a cell, tissue, organ, or portion of any of the above.

1. A method for detecting the presence of human ICOS (inducible T-cell costimulatory molecule) protein, or human CD278 protein or polypeptide in or on the surface of a cell, tissue, organ, or part of any of the above, comprising:

47. 47. The method of claim 46, wherein the at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP comprises a variable heavy chain (VH) having an amino acid sequence comprising SEQ ID NO: 1 and a variable light chain (VL) having an amino acid sequence comprising SEQ ID NO:

2.

48. 48. The method of claim 47, wherein the at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP comprises a heavy chain having an amino acid sequence comprising SEQ ID NO:4 and a light chain having an amino acid sequence comprising SEQ ID NO:

9.

49. 49. The method of any one of claims 46 to 48, comprising contacting the cell, tissue or organ, or a portion of any of the above, with two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs, or a mixture of two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs.

50. 50. The method of any one of claims 46 to 49, wherein the contacting step comprises the use of an immunohistochemistry (IHC) assay.

51. 51. The method of any one of claims 46 to 50, further comprising the step of contacting the Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP specifically bound to the human ICOS protein or human CD278 protein or polypeptide with a detectable agent, thereby indicating or conveying specific binding of the Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP to the human ICOS protein or human CD278 protein or polypeptide.

52. 52. The method of claim 51, wherein the detectable agent specifically binds to an Ab, or an Ag-binding fragment thereof, or a monomeric or dimeric ABP.

53. 53. The method of any one of claims 46 to 52, wherein the cell, tissue, organ, or portion of any of the above is or comprises an early B cell, a pro-B cell, a pre-B lymphocyte, a mature B lymphocyte, a follicular center cell, or a cell in a tonsil, organ, lymph node germinal center, bone marrow stem cell, bone marrow hematopoietic cell, T lymphocyte, parafollicular T lymphocyte, a subpopulation of parafollicular T lymphocytes, liver bile canalicular cell, kidney glomerular cell, proximal tubule cell, breast myoepithelial cell, stromal cell around or associated with an invasive tumor cell, kidney cell, cerebellar cell, prostate cell, pancreatic cell, bone marrow cell, or epithelial cell.

54. 54. The method of claim 53, wherein the epithelial cell is a brain, lung, intestinal, kidney, breast, or placental epithelial cell.

55. 55. The method of any one of claims 46 to 54, wherein the organ is the liver, prostate, brain, pancreas, bladder, colon, esophagus, kidney, skin or lung.

56. 56. The method of any one of claims 46 to 55, wherein the cell, tissue, organ or part of any of the above is or comprises a cancer or tumor cell, or a cancer cell or carcinoid tumor cell.

57. 53. The method of claim 52, wherein said cancer or tumor cell is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer or colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma or leukemia cell, or a mycosis fungoides cell.

58. 50. The method of claim 49, wherein the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma, or mantle cell lymphoma.

59. 59. The method of claim 58, wherein the B-cell lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

60. 60. The method of claim 59, wherein the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL).

61. 57. The method of claim 56, wherein the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells.

62. 1. A method for detecting or diagnosing cancer or tumors, comprising:

62. The method of any one of claims 46 to 61, comprising detecting the expression or presence of human ICOS (inducible T-cell costimulatory molecule) protein, or human CD278 protein or polypeptide in or on the surface of a cell, tissue or organ sample, Detection of specific binding of an Ab, or Ag-binding fragment thereof, or a monomeric or dimeric ABP to human ICOS (inducible T-cell costimulatory molecule) protein, or human CD278 protein or polypeptide within or on the surface of a cell, tissue, or organ, or part of any of the above, detects or diagnoses, or aids in the detection or diagnosis of, cancer or tumor; method.

63. 63. The method of claim 62, wherein the cancer or tumor is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), or a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma cell or a leukemia cell, or a mycosis fungoides cell.

64. 64. The method of claim 63, wherein the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma, or mantle cell lymphoma.

65. 65. The method of claim 64, wherein the B-cell lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

66. 66. The method of claim 65, wherein the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL).

67. 64. The method of claim 63, wherein the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells.

68. 68. The method of any one of claims 62 to 67, wherein the cell, tissue or organ sample is derived from an individual in need thereof or an individual who has a relatively high risk of having cancer or a tumor or who has a family history of cancer or a tumor.

69. 69. The method of any one of claims 62 to 68, wherein the detecting comprises performing an immunohistochemistry (IHC) assay.

70. 70. The method of any one of claims 62 to 69, wherein at least two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs are used to contact the cell, tissue or organ sample.

71. 71. The method of claim 70, wherein at least one of the two Abs, or Ag-binding fragments thereof, or monomeric or dimeric ABPs comprises a variable heavy chain (VH) having an amino acid sequence comprising SEQ ID NO: 1 and a variable light chain (VL) having an amino acid sequence comprising SEQ ID NO:

2.

72. 72. The method of claim 71, wherein the at least one Ab, or Ag-binding fragment thereof, or monomeric or dimeric ABP comprises a heavy chain having an amino acid sequence comprising SEQ ID NO:4 and a light chain having an amino acid sequence comprising SEQ ID NO:

9.

73. 73. A method for treating, ameliorating or preventing cancer or tumors, comprising initially detecting or diagnosing cancer or tumors using the method of any one of claims 62 to 72, and subsequently treating an individual in need thereof for the treatment, amelioration or prevention of cancer or tumors.

74. 74. The method of claim 73, wherein said cancer or tumor is or comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma or leukemia cell, or a mycosis fungoides cell.

75. 75. The method of claim 74, wherein the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma, or mantle cell lymphoma.

76. 76. The method of claim 75, wherein the B-cell lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

77. 77. The method of claim 76, wherein the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL).

78. 75. The method of claim 74, wherein the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells.

79. 79. The method of any one of claims 73 to 78, wherein the cell, tissue or organ sample is derived from an individual in need thereof, and optionally the individual in need thereof is an individual at relatively high risk of having tumor cancer or has a family history of cancer or tumor.

80. 42. Use of at least one recombinant antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) according to any one of claims 1 to 35, or encoded by a nucleic acid according to any one of claims 36 to 41, for detecting or diagnosing cancer, or treating, ameliorating or preventing cancer.

81. 81. The use of claim 80, wherein the cancer or tumor is, comprises or is derived from a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or Epstein-Barr-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a kidney or renal cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma or leukemia cell, or a mycosis fungoides cell.

82. 82. The method of claim 81, wherein the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma, or mantle cell lymphoma.

83. 83. The method of claim 82, wherein the B-cell lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

84. 84. The method of claim 83, wherein the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL).

85. 82. The method of claim 81, wherein the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells.

86. 86. The use of any one of claims 80 to 85, wherein the detection comprises performing an immunohistochemistry (IHC) assay.

87. 40. A recombinant antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) according to any one of claims 1 to 35, or according to any one of the preceding claims, for use in the detection or diagnosis of, or the treatment, amelioration or prevention of, cancer.

88. Optionally, the cancer or tumor is a cancer cell (optionally a squamous cell carcinoma cell), a breast cancer cell, a colon cancer cell or a colorectal cancer cell, a melanoma cell (optionally a malignant melanoma cell) or a multiple myeloma cell, a plasmacytoma cell, a lymphoma cell, a bladder or urothelial cancer cell, a cervical cancer cell, an ovarian cancer cell, an esophageal cancer or esophageal squamous cell; a malignant pleural mesothelioma cell, a prostate cancer cell, a cell from a microsatellite instability-high / mismatch repair deficient tumor, a human papillomavirus-positive or EPS 81. The recombinant antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) of claim 80, which is, comprises or is derived from a Timon-positive tumor cell, a hepatocellular carcinoma or liver cancer cell, a lung cancer (optionally a non-small cell lung cancer (NSCLC)) cell, a gastric cancer cell, a renal or kidney cancer cell, a pancreatic cancer cell, a breast cancer cell (optionally a triple-negative breast cancer cell), a lymphoma or leukemia cell, or a mycosis fungoides cell.

89. 89. The method of claim 88, wherein the lymphoma or leukemia cells are or are derived from B-cell lymphoma, acute lymphoblastic leukemia (ALL) cells, angioimmunoblastic T-cell lymphoma cells, cutaneous T-cell lymphoma, chronic myeloid leukemia in blast crisis, diffuse large B-cell lymphoma cells, hairy cell leukemia cells, follicular lymphoma cells, Burkitt's lymphoma, diffuse large B-cell lymphoma, or mantle cell lymphoma.

90. 90. The method of claim 89, wherein the B-cell lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

91. 91. The method of claim 90, wherein the non-Hodgkin's lymphoma is follicular lymphoma, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Burkitt's lymphoma or mantle cell lymphoma (MCL).

92. 89. The method of claim 88, wherein the cancer cells are head and neck squamous cell carcinoma (HNSCC) or basal cell carcinoma (BCC) cells.

93. 93. The recombinant antibody (Ab), or antigen (Ag)-binding fragment thereof, or monomeric or dimeric antigen-binding protein (ABP) of any one of claims 87 to 92, wherein the detecting or diagnosing step comprises performing an immunohistochemistry (IHC) assay.

94. A kit comprising a chimeric or recombinant antibody according to any one of claims 1 to 35 or any one of the preceding claims; a chimeric or recombinant nucleic acid according to any one of claims 36 to 41; or an expression cassette, vector, recombinant virus, artificial chromosome, cosmid or plasmid according to claim 42; or a cell according to any one of claims 43 to 45.

95. 95. The kit of claim 94, comprising components required for an immunohistochemistry (IHC) assay and / or instructions for carrying out the method of any one of the preceding claims.

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