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US-20260125465-A1 - VHH POLYPEPTIDES THAT BIND TO MESOTHELIN, COMPOSITIONS AND METHODS OF USE THEREOF

US20260125465A1US 20260125465 A1US20260125465 A1US 20260125465A1US-20260125465-A1

Abstract

Single domain VHH polypeptides (antibodies) that bind mesothelin, VHH polypeptide products, methods, cells, pharmaceutical compositions, and kits. The VHH polypeptides may be recombinantly produced and expressed. Provided are also chimeric antigen receptor (CAR) polypeptides comprising the VHH polypeptides and CAR immune effector cells comprising the expressing the same.

Inventors

  • Robert Manguso
  • Gabriel Griffin
  • Nelson KNUDSEN
  • Hans Pope

Assignees

  • THE BROAD INSTITUTE, INC.
  • THE GENERAL HOSPITAL CORPORATION
  • DANA-FARBER CANCER INSTITUTE, INC.

Dates

Publication Date
20260507
Application Date
20251210

Claims (20)

  1. 1 . A VH-heavy chain only (VHH) polypeptide or an antigen binding portion thereof that specifically binds to mesothelin, wherein the binding protein or the antigen binding portion thereof comprises three Complementarity Determining Regions (CDRs): CDR1, CDR2 and CDR3, which are structurally positioned between four camelid VHH framework (FR) regions (FR1-FR4) as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4; wherein the three CDRs are selected from: CDR1 comprising the amino acid sequence GRTFSSYA (SEQ ID NO: 1); CDR2 comprising the amino acid sequence ICWSGGNT (SEQ ID NO: 2); and CDR3 comprising the amino acid sequence NERTTVLPTGAMDY (SEQ ID NO: 3); CDR1 comprising the amino acid sequence GSMFSINA (SEQ ID NO: 4); CDR2 comprising the amino acid sequence MTSGGST (SEQ ID NO: 5); and CDR3 comprising the amino acid sequence NGGWSLAMDY (SEQ ID NO: 6); CDR1 comprising the amino acid sequence GFTLDYYA (SEQ ID NO: 7); CDR2 comprising the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 comprising the amino acid sequence AAAGGYGNSSRY (SEQ ID NO: 9); CDR1 comprising the amino acid sequence GSIFSVNA (SEQ ID NO: 10); CDR2 comprising the amino acid sequence INTGGGST (SEQ ID NO: 11); and CDR3 comprising the amino acid sequence AAEDFGNSKTY (SEQ ID NO: 12); CDR1 comprising the amino acid sequence GFPYFSCC (SEQ ID NO: 13); CDR2 comprising the amino acid sequence ISSDGST (SEQ ID NO: 14); and CDR3 comprising the amino acid sequence AASPRQLGPYYAMDY (SEQ ID NO: 15); CDR1 comprising the amino acid sequence GFTLDNYA (SEQ ID NO: 16); CDR2 comprising the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 comprising the amino acid sequence AGVGDYGRRA (SEQ ID NO: 17); and CDR1 comprising the amino acid sequence GFTFDDSD (SEQ ID NO: 18); CDR2 comprising the amino acid sequence ISSDGST (SEQ ID NO: 14); and CDR3 comprising the amino acid sequence RTMASRIGC (SEQ ID NO: 19).
  2. 2 . The VHH polypeptide of claim 1 , wherein i) FR1 comprises the following amino acid sequence: X 1 X 2 QLVESGGGX 3 VQX 4 GX 5 X 6 LRLX 7 CX 8 AS (SEQ ID NO: 20), wherein X 1 is E, D, or Q, X 2 is V or L, X 3 is L or S, X 4 is A or P, X 5 is E or G, X 6 is S or T, X 7 is S or T, and X 8 is A, T, or V; ii) FR2 comprises the following amino acid sequence: X a X b X 13 X 14 RQX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 VX 23 X c , wherein X a is I, M, or V, X b is A, G, or S, X 13 is W or Y, X 14 is F, H, or Y, X 15 is A, I, or X, X 16 is P or S, X 17 is G or T, X 18 is D, K, or E, X 19 is D, E, or Q, X 20 is C or R, X 21 is E or N, X 22 is F, G, L, or P, X 23 is S or A, and X c is A, S, T, or Y; iii) FR3 comprises the following amino acid sequence: X d YAX e X f VX g GRFTX 24 SX 25 X 26 X 27 AX 28 X 29 X 30 X 31 X 32 LQMX 33 SLKX 34 EDT X 35 X 36 YX 37 C (SEQ ID NO: 21), wherein X d is F, H, I, N, or Y, X e is A or D, X f is S or T, X g is K or R, X 24 is I or V, X 25 is G, K, R, Q, or W, X 26 is D or G, X 27 is N or T, X 28 is K, N, or R, X 29 is N, H, or Q, X 30 is T or S, X 31 is V or L, X 32 is F or Y, X 33 is N, S, or T, X 34 is P or S, X 35 is A or G, X 36 is I or V, and X 37 is F, I, S, or Y; and iv) FR4 comprises the following amino acid sequence: X 40 GQGTX 41 VTVX 42 X 43 (SEQ ID NO: 22), wherein X 40 is M or W, X 41 is L or S, X 42 is null or S, and X 43 is null or S.
  3. 3 . The VHH polypeptide of claim 1 , wherein the polypeptide binds a mesothelin antigen with a K d of less than 12 nM.
  4. 4 . A polypeptide that specifically binds to mesothelin, wherein the polypeptide or a mesothelin-binding portion thereof has at least 85% amino acid sequence identity to a (SEQ ID NO: 55) QVQLVESGGGLVQAGGSLRLSCVASGRTFSSYAMGWFRQSPGKEREFVA AICWSGGNTYYADSVKGRFTISGDNAKNSVYLQMNSLKPEDTAVYICNE RTTVLPTGAMDYWGQGTSVTVSS; (SEQ ID NO: 56) QVQLVESGGGLVQPGGSLRLSCAASGSMFSINAVAWYRQAPGEQREPVA AMTSGGSTIYADSVKGRFTISRDNAKNTVYLQMSSLKPEDTAVYYCNGG WSLAMDYWGQGTSVTVS; (SEQ ID NO: 57) QLQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREGVS YISSSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYSCAA AGGYGNSSRYWGQGTSVTVS; (SEQ ID NO: 58) QVQLVESGGGLVQPGGSLRLSCAASGSIFSVNAMGYYRQISTKQRNLVA AINTGGGSTYYADSVKGRFTISWDNANNTLFLQMNSLKSEDTAVYYCAA EDFGNSKTYWGQGTLVTVS; (SEQ ID NO: 4476) DVQLVESGGGLVQAGGSLRLSCAASGFPYFSCCMSWHRQAPGKDRELVS SISSDGSTHYADSVRGRFTISKGNARNTLYLQMNSLKPEDTAVYFCAAS PRQLGPYYAMDYWGQGTSVTVS; (SEQ ID NO: 60) QLQLVESGGGLVQPGGSLRLSCAASGFTLDNYAIGWFRQAPGKEREGVS SISSSGGSTNYADSVKGRFTVSRDNAKHTVYLQMNSLKPEDTAVYYCAG VGDYGRRAMGQGTSVTVS; (SEQ ID NO: 61) EVQLVESGGGSVQAGETLRLSCTASGFTFDDSDMGWYRQAPGDECELVS TISSDGSTNYADSVKGRFTISQDNAKNTVYLQMTSLKPEDTAIYSCRTM ASRIGCWGQGTLVTVS.
  5. 5 . A chimeric antigen receptor polypeptide (CAR) comprising the polypeptide of claim 1 .
  6. 6 . The CAR of claim 5 , wherein the polypeptide comprises an amino acid sequence with at least about 85% identity to one of the following sequences: (SEQ ID NO: 23) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQPGGSLRLSCAASGSMFSINAVAWYRQAPGE QREPVAAMTSGGSTIYADSVKGRFTISRDNAKNTVYLQMSSLKPEDTAVYYCNGGWSLAMDY WGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGVL ACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELASL RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 24) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQPGGSLRLSCAASGSIFSVNAMGYYRQISTK QRNLVAAINTGGGSTYYADSVKGRFTISWDNANNTLFLQMNSLKSEDTAVYYCAAEDFGNSK TYWGQGTLVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGG VLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELA SLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 25) MLRLLLALNLFPSIQVTGGDVQLVESGGGLVQAGGSLRLSCAASGFPYFSCCMSWHRQAPGK DRELVSSISSDGSTHYADSVRGRFTISKGNARNTLYLQMNSLKPEDTAVYFCAASPRQLGPY YAMDYWGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVV VGGVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC ELASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQE GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 26) MLRLLLALNLFPSIQVTGGQLQLVESGGGLVQPGGSLRLSCAASGFTLDNYAIGWFRQAPGK EREGVSSISSSGGSTNYADSVKGRFTVSRDNAKHTVYLQMNSLKPEDTAVYYCAGVGDYGRR AMGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGV LACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELAS LRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYN ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 27) MLRLLLALNLFPSIQVTGGQLQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGK EREGVSYISSSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYSCAAAGGYGNS SRYWGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVG GVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL ASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGL YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 28) MLRLLLALNLFPSIQVTGGEVQLVESGGGSVQAGETLRLSCTASGFTFDDSDMGWYRQAPGD ECELVSTISSDGSTNYADSVKGRFTISQDNAKNTVYLQMTSLKPEDTAIYSCRTMASRIGCW GQGTLVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGVLA CYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELASLR VKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; and (SEQ ID NO: 29) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQAGGSLRLSCVASGRTFSSYAMGWFRQSPGK EREFVAAICWSGGNTYYADSVKGRFTISGDNAKNSVYLQMNSLKPEDTAVYICNERTTVLPT GAMDYWGQGTSVTVSSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLV VVGGVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGG CELASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS.
  7. 7 . The CAR of claim 5 , wherein the CAR comprises in order from N-terminus to C-terminus a CD28 signal peptide, the polypeptide of claim 1 , a CD8 hinge domain, a CD28 transmembrane domain, a CD28 cytoplasmic domain, and a CD3ζ domain.
  8. 8 . A polynucleotide encoding the VHH polypeptide of claim 1 .
  9. 9 . The polynucleotide of claim 8 , wherein the polynucleotide comprises a sequence that has at least 85% identity to a sequence selected from the group consisting of. (SEQ ID NO: 69) CAAGTTCAGCTTGTGGAGTCAGGCGGTGGACTCGTTCAAGCCGGAGGCTCACTGCGGTTGTC TTGTGTCGCATCTGGTCGAACCTTCTCAAGTTATGCTATGGGGTGGTTCCGCCAGTCTCCTG GTAAAGAGCGGGAATTTGTCGCAGCAATTTGTTGGTCTGGTGGTAACACTTACTATGCTGAT TCAGTAAAAGGTCGATTCACCATATCAGGGGATAATGCAAAAAATTCTGTCTATCTCCAAAT GAACTCTCTGAAGCCTGAAGATACTGCTGTGTATATCTGTAATGAGAGGACTACGGTACTAC CTACGGGTGCTATGGACTACTGGGGTCAAGGGACCTCAGTCACCGTCTCCTCG; (SEQ ID NO: 70) CAAGTTCAGCTTGTCGAGAGTGGTGGAGGATTGGTGCAGCCAGGCGGATCTCTCAGACTTTC CTGCGCCGCCAGTGGTTCTATGTTTTCCATAAATGCAGTGGCCTGGTACAGGCAAGCACCAG GCGAGCAAAGGGAACCGGTAGCCGCAATGACCTCTGGAGGTAGTACAATTTACGCTGATAGC GTCAAGGGACGATTCACAATATCACGAGACAATGCCAAGAACACTGTCTACCTTCAAATGAG CAGTTTGAAACCTGAGGATACAGCAGTATACTACTGCAATGGAGGATGGTCACTGGCTATGG ACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCC; (SEQ ID NO: 71) CAGCTTCAACTGGTAGAGAGTGGTGGAGGACTTGTTCAGCCTGGAGGGTCCCTTAGACTTAG TTGCGCTGCCAGTGGGTTCACCCTGGACTACTACGCCATTGGCTGGTTTCGACAGGCCCCAG GGAAAGAGCGAGAGGGGGTCTCTTACATCAGTAGTTCCGGTGGTTCCACTAACTACGCTGAT AGTGTGAAGGGGAGGTTTACTATTTCTCGGGATAATGCAAAAAATACCGTGTACCTGCAAAT GAATAGCCTCAAACCAGAAGACACAGGCGTTTATTCTTGCGCAGCAGCTGGGGGCTATGGTA ACTCCTCTCGCTACTGGGGTCAAGGAACCTCAGTCACCGTCTCC; (SEQ ID NO: 72) CAGGTTCAGCTGGTGGAGTCCGGCGGAGGTCTTGTTCAGCCCGGAGGTTCCCTGCGCCTCTC TTGTGCAGCTTCTGGTTCCATTTTCTCAGTCAATGCAATGGGCTACTACAGACAAATTTCCA CAAAGCAGCGCAACTTGGTCGCCGCAATAAATACTGGTGGTGGCTCGACTTATTACGCCGAT AGTGTCAAAGGACGATTTACTATAAGTTGGGACAACGCAAACAATACTTTGTTCCTCCAAAT GAATAGCCTCAAATCAGAAGACACTGCCGTCTACTACTGTGCAGCAGAGGACTTTGGTAACT CGAAAACTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCT; (SEQ ID NO: 73) GACGTACAACTTGTGGAATCAGGTGGGGGTCTCGTTCAAGCTGGTGGGTCACTGCGGCTTTC TTGCGCTGCAAGTGGGTTCCCTTATTTTTCCTGCTGTATGAGCTGGCATCGCCAAGCTCCTG GAAAAGATCGGGAACTGGTCTCCAGTATTTCATCTGACGGGTCAACACATTACGCTGATAGC GTCAGGGGGAGGTTTACTATTTCTAAAGGAAATGCAAGAAACACACTCTACCTCCAGATGAA CAGTCTGAAGCCCGAAGACACCGCCGTGTATTTCTGTGCAGCTTCCCCTAGACAGCTCGGGC CTTACTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCC; (SEQ ID NO: 74) CAGCTTCAACTGGTAGAGAGTGGTGGAGGACTTGTTCAGCCTGGAGGGTCCCTTAGACTTAG TTGCGCTGCCAGTGGGTTCACCCTGGACAACTACGCCATTGGCTGGTTTCGACAGGCCCCAG GGAAAGAGCGAGAGGGGGTCTCTAGCATCAGTAGTTCCGGTGGTTCCACCAACTATGCTGAT AGTGTGAAGGGGAGGTTTACTGTTTCTCGGGATAATGCAAAACATACCGTGTACCTGCAAAT GAATAGCCTCAAACCAGAAGACACAGCCGTCTATTATTGCGCAGGAGTTGGGGACTACGGTA GAAGGGCGATGGGTCAAGGCACCTCAGTCACCGTCTCC; and (SEQ ID NO: 75) GAAGTTCAGCTTGTTGAATCAGGCGGCGGAAGTGTCCAAGCTGGCGAAACCCTTCGGCTCTC CTGCACCGCATCCGGCTTCACATTCGATGATTCAGATATGGGCTGGTACAGGCAGGCTCCTG GTGACGAATGTGAGCTGGTATCCACAATCTCCAGCGATGGCAGCACAAATTATGCTGACTCT GTTAAAGGGCGATTTACCATCTCTCAAGATAACGCAAAGAACACCGTGTATCTGCAGATGAC CTCATTGAAGCCAGAGGATACTGCCATATATTCATGCAGAACAATGGCCTCGAGGATTGGTT GCTGGGGCCAAGGGACTCTGGTCACTGTCTCT.
  10. 10 . The polynucleotide of claim 8 , wherein the polynucleotide comprises a sequence that has at least 85% identity to a sequence selected from the group consisting of: (SEQ ID NO: 80) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGCAAGT TCAGCTTGTCGAGAGTGGTGGAGGATTGGTGCAGCCAGGCGGATCTCTCAGACTTTCCTGCG CCGCCAGTGGTTCTATGTTTTCCATAAATGCAGTGGCCTGGTACAGGCAAGCACCAGGCGAG CAAAGGGAACCGGTAGCCGCAATGACCTCTGGAGGTAGTACAATTTACGCTGATAGCGTCAA GGGACGATTCACAATATCACGAGACAATGCCAAGAACACTGTCTACCTTCAAATGAGCAGTT TGAAACCTGAGGATACAGCAGTATACTACTGCAATGGAGGATGGTCACTGGCTATGGACTAC TGGGGTCAAGGAACCTCAGTCACCGTCTCCCCGACGCCAGCGCCAACTATTGCGAGTCAGCC TCTCAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCGCAGTGCACACGAGGGGGC TGGACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTG GCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAAACGGGGCAG AAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGG AAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGGCTAGCCTG AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTA TAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGG ACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAA CTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAG GGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACG CCCTTCACATGCAGGCCCTGCCCCCTCGCGCTAGC; (SEQ ID NO: 81) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGCAGGT TCAGCTGGTGGAGTCCGGCGGAGGTCTTGTTCAGCCCGGAGGTTCCCTGCGCCTCTCTTGTG CAGCTTCTGGTTCCATTTTCTCAGTCAATGCAATGGGCTACTACAGACAAATTTCCACAAAG CAGCGCAACTTGGTCGCCGCAATAAATACTGGTGGTGGCTCGACTTATTACGCCGATAGTGT CAAAGGACGATTTACTATAAGTTGGGACAACGCAAACAATACTTTGTTCCTCCAAATGAATA GCCTCAAATCAGAAGACACTGCCGTCTACTACTGTGCAGCAGAGGACTTTGGTAACTCGAAA ACTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTCCGACGCCAGCGCCAACTATTGCGAG TCAGCCTCTCAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCGCAGTGCACACGA GGGGGCTGGACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGGTGGA GTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAAACG GGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTC AAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGGCT AGCCTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCA GCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTG GCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTAC AATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCG CCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCT ACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCGCTAGC; (SEQ ID NO: 82) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGGACGT ACAACTTGTGGAATCAGGTGGGGGTCTCGTTCAAGCTGGTGGGTCACTGCGGCTTTCTTGCG CTGCAAGTGGGTTCCCTTATTTTTCCTGCTGTATGAGCTGGCATCGCCAAGCTCCTGGAAAA GATCGGGAACTGGTCTCCAGTATTTCATCTGACGGGTCAACACATTACGCTGATAGCGTCAG GGGGAGGTTTACTATTTCTAAAGGAAATGCAAGAAACACACTCTACCTCCAGATGAACAGTC TGAAGCCCGAAGACACCGCCGTGTATTTCTGTGCAGCTTCCCCTAGACAGCTCGGGCCTTAC TATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCCCGACGCCAGCGCCAAC TATTGCGAGTCAGCCTCTCAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCGCAG TGCACACGAGGGGGCTGGACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTGGTG GTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGT GAGGAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTAC AAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGT GAACTGGCTAGCCTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGG CCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACA AGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAA GGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAA AGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCA AGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCGCTAGC; (SEQ ID NO: 83) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGCAGCT TCAACTGGTAGAGAGTGGTGGAGGACTTGTTCAGCCTGGAGGGTCCCTTAGACTTAGTTGCG CTGCCAGTGGGTTCACCCTGGACAACTACGCCATTGGCTGGTTTCGACAGGCCCCAGGGAAA GAGCGAGAGGGGGTCTCTAGCATCAGTAGTTCCGGTGGTTCCACCAACTATGCTGATAGTGT GAAGGGGAGGTTTACTGTTTCTCGGGATAATGCAAAACATACCGTGTACCTGCAAATGAATA GCCTCAAACCAGAAGACACAGCCGTCTATTATTGCGCAGGAGTTGGGGACTACGGTAGAAGG GCGATGGGTCAAGGCACCTCAGTCACCGTCTCCCCGACGCCAGCGCCAACTATTGCGAGTCA GCCTCTCAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCGCAGTGCACACGAGGG GGCTGGACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTC CTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAAACGGGG CAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAG AGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGGCTAGC CTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCT CTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCC GGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAAT GAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCG GAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACG ACGCCCTTCACATGCAGGCCCTGCCCCCTCGCGCTAGC; (SEQ ID NO: 84) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGCAGCT TCAACTGGTAGAGAGTGGTGGAGGACTTGTTCAGCCTGGAGGGTCCCTTAGACTTAGTTGCG CTGCCAGTGGGTTCACCCTGGACTACTACGCCATTGGCTGGTTTCGACAGGCCCCAGGGAAA GAGCGAGAGGGGGTCTCTTACATCAGTAGTTCCGGTGGTTCCACTAACTACGCTGATAGTGT GAAGGGGAGGTTTACTATTTCTCGGGATAATGCAAAAAATACCGTGTACCTGCAAATGAATA GCCTCAAACCAGAAGACACAGGCGTTTATTCTTGCGCAGCAGCTGGGGGCTATGGTAACTCC TCTCGCTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCCCGACGCCAGCGCCAACTATTGC GAGTCAGCCTCTCAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCGCAGTGCACA CGAGGGGGCTGGACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGGT GGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAA ACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTA CTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG GCTAGCCTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAA CCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGAC GTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTG TACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGA GCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACA CCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCGCTAGC; (SEQ ID NO: 85) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGGAAGT TCAGCTTGTTGAATCAGGCGGCGGAAGTGTCCAAGCTGGCGAAACCCTTCGGCTCTCCTGCA CCGCATCCGGCTTCACATTCGATGATTCAGATATGGGCTGGTACAGGCAGGCTCCTGGTGAC GAATGTGAGCTGGTATCCACAATCTCCAGCGATGGCAGCACAAATTATGCTGACTCTGTTAA AGGGCGATTTACCATCTCTCAAGATAACGCAAAGAACACCGTGTATCTGCAGATGACCTCAT TGAAGCCAGAGGATACTGCCATATATTCATGCAGAACAATGGCCTCGAGGATTGGTTGCTGG GGCCAAGGGACTCTGGTCACTGTCTCTCCGACGCCAGCGCCAACTATTGCGAGTCAGCCTCT CAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCGCAGTGCACACGAGGGGGCTGG ACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCT TGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTGAGGAAACGGGGCAGAAA GAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAG ATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGGCTAGCCTGAGA GTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAA CGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACC CTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTG CAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGG CAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCC TTCACATGCAGGCCCTGCCCCCTCGCGCTAGC; and (SEQ ID NO: 86) ATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGCAAGT TCAGCTTGTGGAGTCAGGCGGTGGACTCGTTCAAGCCGGAGGCTCACTGCGGTTGTCTTGTG TCGCATCTGGTCGAACCTTCTCAAGTTATGCTATGGGGTGGTTCCGCCAGTCTCCTGGTAAA GAGCGGGAATTTGTCGCAGCAATTTGTTGGTCTGGTGGTAACACTTACTATGCTGATTCAGT AAAAGGTCGATTCACCATATCAGGGGATAATGCAAAAAATTCTGTCTATCTCCAAATGAACT CTCTGAAGCCTGAAGATACTGCTGTGTATATCTGTAATGAGAGGACTACGGTACTACCTACG GGTGCTATGGACTACTGGGGTCAAGGGACCTCAGTCACCGTCTCCTCGCCGACGCCAGCGCC AACTATTGCGAGTCAGCCTCTCAGTCTGCGACCTGAGGCTTGTCGACCAGCAGCCGGAGGCG CAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATCCTTCTAAGCCCTTTTGGGTGCTGGTG GTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTG GGTGAGGAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAG TACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGA TGTGAACTGGCTAGCCTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCA GGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGG ACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAG GAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGAT GAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCA CCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCGCTAGC.
  11. 11 . A vector comprising the polynucleotide of claim 8 .
  12. 12 . A cell comprising the polynucleotide of claim 8 .
  13. 13 . A pharmaceutical composition comprising an effective amount of the polypeptide of claim 1 , and a pharmaceutically acceptable excipient, carrier, or diluent.
  14. 14 . A method for treating a subject having a neoplasia, the method comprising administering to the subject the pharmaceutical composition of claim 13 .
  15. 15 . A kit comprising the polypeptide of claim 1 , and a container, for use in treating a subject having a neoplasia.
  16. 16 . A method of detecting mesothelin or a fragment thereof in a sample, the method comprising: contacting the sample with at least one detectably labeled VHH binding protein or an antigen binding fragment thereof that specifically binds to mesothelin or a peptide thereof, wherein the binding protein or the antigen binding fragment thereof comprises three Complementarity Determining Regions (CDRs), CDR1, CDR2, and CDR3 structurally positioned between four framework (FR) regions (FR1-FR4) as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4; wherein the three CDRs are selected from: CDR1 comprising the amino acid sequence GRTFSSYA (SEQ ID NO: 1); CDR2 comprising the amino acid sequence ICWSGGNT (SEQ ID NO: 2); and CDR3 comprising the amino acid sequence NERTTVLPTGAMDY (SEQ ID NO: 3); CDR1 comprising the amino acid sequence GSMFSINA (SEQ ID NO: 4); CDR2 comprising the amino acid sequence MTSGGST (SEQ ID NO: 5); and CDR3 comprising the amino acid sequence NGGWSLAMDY (SEQ ID NO: 6); CDR1 comprising the amino acid sequence GFTLDYYA (SEQ ID NO: 7); CDR2 comprising the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 comprising the amino acid sequence AAAGGYGNSSRY (SEQ ID NO: 9); CDR1 comprising the amino acid sequence GSIFSVNA (SEQ ID NO: 10); CDR2 comprising the amino acid sequence INTGGGST (SEQ ID NO: 11); and CDR3 comprising the amino acid sequence AAEDFGNSKTY (SEQ ID NO: 12); CDR1 comprising the amino acid sequence GFPYFSCC (SEQ ID NO: 13); CDR2 comprising the amino acid sequence ISSDGST (SEQ ID NO: 14); and CDR3 comprising the amino acid sequence AASPRQLGPYYAMDY (SEQ ID NO: 15); CDR1 comprising the amino acid sequence GFTLDNYA (SEQ ID NO: 16); CDR2 comprising the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 comprising the amino acid sequence AGVGDYGRRA (SEQ ID NO: 17); and CDR1 comprising the amino acid sequence GFTFDDSD (SEQ ID NO: 18); CDR2 comprising the amino acid sequence ISSDGST (SEQ ID NO: 14); and CDR3 comprising the amino acid sequence RTMASRIGC (SEQ ID NO: 19); and wherein i) FR1 comprises the following amino acid sequence: X 1 X 2 QLVESGGGX 3 VQX 4 GX 5 X 6 LRLX 7 CX 8 AS (SEQ ID NO: 20), wherein X 1 is E, D, or Q, X 2 is V or L, X 3 is L or S, X 4 is A or P, X 5 is E or G, X 6 is S or T, X 7 is S or T, and X 8 is A, T, or V; ii) FR2 comprises the following amino acid sequence: X a X b X 13 X 14 RQX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 VX 23 X c , wherein X a is I, M, or V, X b is A, G, or S, X 13 is W or Y, X 14 is F, H, or Y, X 15 is A, I, or X, X 16 is P or S, X 17 is G or T, X 18 is D, K, or E, X 19 is D, E, or Q, X 20 is C or R, X 21 is E or N, X 22 is F, G, L, or P, X 23 is S or A, and X c is A, S, T, or Y; iii) FR3 comprises the following amino acid sequence: X d YAX e X f VX g GRFTX 24 SX 25 X 26 X 27 AX 28 X 29 X 30 X 31 X 32 LQMX 33 SLKX 34 EDT X 35 X 36 YX 37 C (SEQ ID NO: 21), wherein X d is F, H, I, N, or Y, X e is A or D, X f is S or T, X g is K or R, X 24 is I or V, X 25 is G, K, R, Q, or W, X 26 is D or G, X 27 is N or T, X 28 is K, N, or R, X 29 is N, H, or Q, X 30 is T or S, X 31 is V or L, X 32 is F or Y, X 33 is N, S, or T, X 34 is P or S, X 35 is A or G, X 36 is I or V, and X 37 is F, I, S, or Y; and iv) FR4 comprises the following amino acid sequence: X 40 GQGTX 41 VTVX 42 X 43 (SEQ ID NO: 22), wherein X 40 is M or W, X 41 is L or S, X 42 is null or S, and X 43 is null or S; and measuring the level of binding of the binding protein to mesothelin in the sample relative to a control to detect or identify the presence of mesothelin in the sample.
  17. 17 . A chimeric antigen receptor (CAR) comprising an amino acid sequence with at least about 95% identity to one of the following sequences: (SEQ ID NO: 23) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQPGGSLRLSCAASGSMFSINAVAWYRQAPGE QREPVAAMTSGGSTIYADSVKGRFTISRDNAKNTVYLQMSSLKPEDTAVYYCNGGWSLAMDY WGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGVL ACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELASL RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 24) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQPGGSLRLSCAASGSIFSVNAMGYYRQISTK QRNLVAAINTGGGSTYYADSVKGRFTISWDNANNTLFLQMNSLKSEDTAVYYCAAEDFGNSK TYWGQGTLVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGG VLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELA SLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 25) MLRLLLALNLFPSIQVTGGDVQLVESGGGLVQAGGSLRLSCAASGFPYFSCCMSWHRQAPGK DRELVSSISSDGSTHYADSVRGRFTISKGNARNTLYLQMNSLKPEDTAVYFCAASPRQLGPY YAMDYWGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVV VGGVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC ELASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQE GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 26) MLRLLLALNLFPSIQVTGGQLQLVESGGGLVQPGGSLRLSCAASGFTLDNYAIGWFRQAPGK EREGVSSISSSGGSTNYADSVKGRFTVSRDNAKHTVYLQMNSLKPEDTAVYYCAGVGDYGRR AMGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGV LACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELAS LRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYN ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 27) MLRLLLALNLFPSIQVTGGQLQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGK EREGVSYISSSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYSCAAAGGYGNS SRYWGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVG GVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL ASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGL YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 28) MLRLLLALNLFPSIQVTGGEVQLVESGGGSVQAGETLRLSCTASGFTFDDSDMGWYRQAPGD ECELVSTISSDGSTNYADSVKGRFTISQDNAKNTVYLQMTSLKPEDTAIYSCRTMASRIGCW GQGTLVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGVLA CYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELASLR VKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; and (SEQ ID NO: 29) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQAGGSLRLSCVASGRTFSSYAMGWFRQSPGK EREFVAAICWSGGNTYYADSVKGRFTISGDNAKNSVYLQMNSLKPEDTAVYICNERTTVLPT GAMDYWGQGTSVTVSSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLV VVGGVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGG CELASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS.
  18. 18 . A T cell expressing the CAR of claim 17 or a polynucleotide encoding the CAR.
  19. 19 . A VH-heavy chain only (VHH) polypeptide or an antigen binding portion thereof that specifically binds to mesothelin, wherein the binding protein or the antigen binding portion thereof comprises an amino acid sequence with at least about 95% identity to one of the following sequences: (SEQ ID NO: 23) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQPGGSLRLSCAASGSMFSINAVAWYRQAPGE QREPVAAMTSGGSTIYADSVKGRFTISRDNAKNTVYLQMSSLKPEDTAVYYCNGGWSLAMDY WGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGVL ACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELASL RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 24) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQPGGSLRLSCAASGSIFSVNAMGYYRQISTK QRNLVAAINTGGGSTYYADSVKGRFTISWDNANNTLFLQMNSLKSEDTAVYYCAAEDFGNSK TYWGQGTLVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGG VLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELA SLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 25) MLRLLLALNLFPSIQVTGGDVQLVESGGGLVQAGGSLRLSCAASGFPYFSCCMSWHRQAPGK DRELVSSISSDGSTHYADSVRGRFTISKGNARNTLYLQMNSLKPEDTAVYFCAASPRQLGPY YAMDYWGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVV VGGVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC ELASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQE GLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 26) MLRLLLALNLFPSIQVTGGQLQLVESGGGLVQPGGSLRLSCAASGFTLDNYAIGWFRQAPGK EREGVSSISSSGGSTNYADSVKGRFTVSRDNAKHTVYLQMNSLKPEDTAVYYCAGVGDYGRR AMGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGV LACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELAS LRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYN ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 27) MLRLLLALNLFPSIQVTGGQLQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGK EREGVSYISSSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTGVYSCAAAGGYGNS SRYWGQGTSVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVG GVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL ASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGL YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; (SEQ ID NO: 28) MLRLLLALNLFPSIQVTGGEVQLVESGGGSVQAGETLRLSCTASGFTFDDSDMGWYRQAPGD ECELVSTISSDGSTNYADSVKGRFTISQDNAKNTVYLQMTSLKPEDTAIYSCRTMASRIGCW GQGTLVTVSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLVVVGGVLA CYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELASLR VKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS; and (SEQ ID NO: 29) MLRLLLALNLFPSIQVTGGQVQLVESGGGLVQAGGSLRLSCVASGRTFSSYAMGWFRQSPGK EREFVAAICWSGGNTYYADSVKGRFTISGDNAKNSVYLQMNSLKPEDTAVYICNERTTVLPT GAMDYWGQGTSVTVSSPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDPSKPFWVLV VVGGVLACYSLLVTVAFIIFWVRKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGG CELASLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRAS. or a polynucleotide encoding the polypeptide.
  20. 20 . A vector comprising the polynucleotide of claim 19 .

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation under 35 U.S.C. § 111(a) of PCT International Patent Application No. PCT/US2024/034108, filed Jun. 14, 2024, designating the United States and published in English, which claims priority to and the benefit of U.S. Provisional Application No. 63/508,189, filed Jun. 14, 2023, the entire contents of each of which are incorporated by reference herein. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The Sequence Listing XML file, created on Aug. 13, 2024, is named 167741-051801_PCT_SL.xml and is 4,390,573 bytes in size. BACKGROUND Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different neoplasias, including lung adenocarcinomas, ovarian carcinomas, and hematological malignancies, including acute myeloid leukemia (AML). Chimeric antigen receptor (CAR) T-cell therapy is one method for treating a neoplasia associated with mesothelin. However, to develop effective CAR-T-cell therapies, it is necessary to identify antigen-binding domains suitable for use in targeting the CAR proteins expressed by the CAR-T-cells to neoplasia cells surface-expressing mesothelin. Accordingly, there is a need for improved antigen binding domains capable of binding a mesothelin antigen. SUMMARY As described below, the disclosure provides single domain VHH polypeptides (nanobodies) that bind mesothelin, VHH polypeptide products, methods of use, cells, pharmaceutical compositions, and kits. The VHH polypeptides may be recombinantly produced and expressed. Provided are also chimeric antigen receptor (CAR) polypeptides comprising the VHH polypeptides and CAR immune effector cells comprising and expressing the same. In another aspect, the disclosure features a VH-heavy chain only (VHH) polypeptide or an antigen binding portion thereof that specifically binds to mesothelin. The binding protein or the antigen binding portion thereof contains three Complementarity Determining Regions (CDRs): CDR1, CDR2 and CDR3, which are structurally positioned between four camelid VHH framework (FR) regions (FR1-FR4) as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The three CDRs are selected from: CDR1 containing the amino acid sequence GRTFSSYA (SEQ ID NO: 1); CDR2 containing the amino acid sequence ICWSGGNT (SEQ ID NO: 2); and CDR3 containing the amino acid sequence NERTTVLPTGAMDY (SEQ ID NO: 3); CDR1 containing the amino acid sequence GSMFSINA (SEQ ID NO: 4); CDR2 containing the amino acid sequence MTSGGST (SEQ ID NO: 5); and CDR3 containing the amino acid sequence NGGWSLAMDY (SEQ ID NO: 6); CDR1 containing the amino acid sequence GFTLDYYA (SEQ ID NO: 7); CDR2 containing the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 containing the amino acid sequence AAAGGYGNSSRY (SEQ ID NO: 9); CDR1 containing the amino acid sequence GSIFSVNA (SEQ ID NO: 10); CDR2 containing the amino acid sequence INTGGGST (SEQ ID NO: 11); and CDR3 containing the amino acid sequence AAEDFGNSKTY (SEQ ID NO: 12); CDR1 containing the amino acid sequence GFPYFSCC (SEQ ID NO: 13); CDR2 containing the amino acid sequence ISSDGST (SEQ ID NO: 14); and CDR3 containing the amino acid sequence AASPRQLGPYYAMDY (SEQ ID NO: 15); CDR1 containing the amino acid sequence GFTLDNYA (SEQ ID NO: 16); CDR2 containing the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 containing the amino acid sequence AGVGDYGRRA (SEQ ID NO: 17); CDR1 containing the amino acid sequence GFTFDDSD (SEQ ID NO: 18); CDR2 containing the amino acid sequence ISSDGST (SEQ ID NO: 14); CDR3 containing the amino acid sequence RTMASRIGC (SEQ ID NO: 19); and any set of CDR1, CDR2, and CDR3 sequences listed in a row of Table 3A. In another aspect, the disclosure features a method of detecting mesothelin or a fragment thereof in a sample. The method involves contacting the sample with at least one detectably labeled VHH binding protein or an antigen binding fragment thereof that specifically binds to mesothelin or a peptide thereof. The binding protein or the antigen binding fragment thereof contains three Complementarity Determining Regions (CDRs), CDR1, CDR2, and CDR3 structurally positioned between four framework (FR) regions (FR1-FR4) as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The three CDRs are selected from: CDR1 containing the amino acid sequence GRTFSSYA (SEQ ID NO: 1); CDR2 containing the amino acid sequence ICWSGGNT (SEQ ID NO: 2); and CDR3 containing the amino acid sequence NERTTVLPTGAMDY (SEQ ID NO: 3); CDR1 containing the amino acid sequence GSMFSINA (SEQ ID NO: 4); CDR2 containing the amino acid sequence MTSGGST (SEQ ID NO: 5); and CDR3 containing the amino acid sequence NGGWSLAMDY (SEQ ID NO: 6); CDR1 containing the amino acid sequence GFTLDYYA (SEQ ID NO: 7); CDR2 containing the amino acid sequence ISSSGGST (SEQ ID NO: 8); and CDR3 containing the amino aci