WHAT IS CLAHVIED IS:
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`CLAIMS
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`1. A modified antibody comprising a formula:
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`A-L-P
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`wherein
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`A is an antibody or antibody fragment that binds to a target antigen,
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`P is a peptide that reduces binding of A to the target antigen at physiological pH and
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`that does not reduce binding of A to the target antigen at acidic pH, and
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`L is a linking moiety that connects A to P at physiological pH and in a tumor
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`microenvironment and L is bound to A outside an antigen binding site.
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`2. The modified antibody of claim 1, wherein at physiological pH P is reversibly bound to A
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`through ionic, electrostatic, hydrophobic, Pi-stacking, and H-bonding interactions, or a combination
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`thereof.
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`3. The modified antibody of claim 1, wherein at physiological pH P is reversibly bound to A
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`at or near the antigen binding site.
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`4. The modified antibody of claim 1, wherein P inhibits the binding of A to the target
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`antigen at physiological pH and P does not inhibit the binding of A to the target antigen at acidic pH.
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`5. The modified antibody of claim 1, wherein in tissue other than the tumor
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`microenvironment, P sterically blocks A from binding to the target antigen.
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`6. The modified antibody of claim 1, wherein at the tumor microenvironment, P is removed
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`from the antigen binding site, and the antigen binding site of A is eXposed.
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`7. The modified antibody of claim 1, wherein the modified antibody has an increased
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`binding affinity for the target antigen in the tumor microenvironment compared to the binding
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`affinity of the modified antibody for the target antigen in a non-tumor microenvironment.
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`8. The modified antibody of claim 1, wherein P comprises a peptide sequence with at least
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`one histidine.
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`9. The modified antibody of claim 8, wherein the histidine forms a binding interaction at or
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`near the antigen binding site of A at physiological pH.
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`10. The modified antibody of claim 1, wherein at acidic pH P is reversibly bound to A in a
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`region of A that is not the antigen binding site.
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`11. The modified antibody of claim 10, wherein at acidic pH P is reversibly bound to A in a
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`region of A that is not the antigen binding site through ionic, electrostatic, hydrophobic, Pi-stacking
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`and H-bonding interactions, or a combination thereof.
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`12. The modified antibody of claim 1, wherein P is resistant to cleavage by a protease.
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`13. The modified antibody of claim 1, wherein physiological pH is about pH 7.4.
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`14. The modified antibody of claim 1, wherein acidic pH is about pH 6.0 to about pH 7.0.
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`15. The modified antibody of claim 1, wherein P comprises a peptide sequence of at least 6
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`amino acids in length.
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`16. The modified antibody of claim 1, wherein P comprises a peptide sequence of at least 10
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`amino acids in length.
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`17. The modified antibody of claim 1, wherein P comprises a peptide sequence of at least 6
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`to 20 amino acids in length.
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`18. The modified antibody of claim 1, wherein P comprises a modified amino acid, a non-
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`natural amino acid, or a modified non-natural amino acids, or combination thereof.
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`19. The modified antibody of claim 18, wherein the modified amino acid or modified non-
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`natural amino acid comprises a post-translational modification.
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`20. The modified antibody of claim 8, wherein at acidic pH P is reversibly bound to L.
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`21. The modified antibody of claim 20, wherein L comprises a peptide sequence with at least
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`one aspartic acid or glutamic acid, or a combination thereof.
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`22. The modified antibody of claim 21, wherein the histidine of P forms an interaction with
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`the aspartic acid or glutamic acid of L.
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`23. The modified antibody of claim 1, wherein L is a peptide sequence having at least 5 to no
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`more than 50 amino acids.
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`24. The modified antibody of claim 1; wherein L has a formula selected from the group
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`consisting of: (GS)n; wherein n is an integer from 6 to 20 (SEQ ID NO: 1); (G2S)n; wherein n is an
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`integer from 4 to 13 (SEQ ID NO: 2); (G3S)n; wherein n is an integer from 3 to 10 (SEQ ID NO: 3);
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`and (G4S)n; wherein n is an integer from 2 to 8 (SEQ ID NO: 4); and (G)n; wherein n is an integer
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`from 12 to 40 (SEQ ID NO: 5).
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`25. The modified antibody of claim 1; wherein L has a formula comprising (GGSGGD)n;
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`wherein n is an integer from 2 to 6 (SEQ ID NO: 8).
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`26. The modified antibody of claim 1; wherein L has a formula comprising (GGSGGE)n;
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`wherein n is an integer from 2 to 6 (SEQ ID NO: 9).
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`27. The modified antibody of claim 1; wherein L has a formula comprising
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`(GGGSGSGGGGS) 11; wherein n is an integer from 1 to 3 (SEQ ID NO: 6).
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`28. The modified antibody of claim 1; wherein L has a formula comprising
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`(GGGGGPGGGGP) 11; wherein n is an integer from 1 to 3 (SEQ ID NO: 7).
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`29. The modified antibody of claim 1; wherein L has a formula selected from (GX)n; wherein
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`X is serine; aspartic acid; glutamic acid; threonine; or proline and n is at least 20 (SEQ ID NO: 24);
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`(GGX)n, wherein X is serine; aspartic acid; glutamic acid; threonine; or proline and n is at least 13
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`(SEQ ID NO: 25); (GGGX)n; wherein X is serine; aspartic acid; glutamic acid; threonine; or proline
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`and n is at least 10 (SEQ ID NO: 26); (GGGGX)n; wherein X is serine; aspartic acid; glutamic acid;
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`threonine; or proline and n is at least 8 (SEQ ID NO: 27); (GZX)n, wherein X is serine; aspartic acid;
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`glutamic acid; threonine; or proline and n is at least 15; and z is between 1 and 20 (SEQ ID NO: 28).
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`30. The modified antibody of claim 1; wherein L is resistant to cleavage by a protease.
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`31. The modified antibody of claim 1; wherein L comprises a modified amino acid.
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`32. The modified antibody of claim 3 1; wherein the modified amino acid comprises a post-
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`translational modification.
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`33. The modified antibody of claim 1; wherein L comprises a non-natural amino acid or a
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`modified non-natural amino acid; or combination thereof.
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`34. The modified antibody of claim 33, wherein the modified non-natural amino acid
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`comprises a post-translational modification.
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`35. The modified antibody of claim 1, wherein the target antigen is selected from the group
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`consisting of: 4-lBB, CTLA4, PD-l, and PD-Ll.
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`36. The modified antibody of claim 35, wherein the target antigen is 4-lBB.
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`37. The modified antibody of claim 35, wherein the target antigen is CTLA4.
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`38. The modified antibody of claim 35, wherein the target antigen is PD-l.
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`39. The modified antibody of claim 35, wherein the target antigen is PD-Ll.
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`40. The modified antibody of claim 1, wherein A is a full length antibody, a single-chain
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`antibody, an Fab fragment, an Fab’ fragment, an (Fab’)2 fragment, an FV fragment, a divalent single
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`chain antibody, bispecific antibody, a trispecific antibody, a tetraspecific antibody, or an antibody
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`drug conjugate.
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`41. The modified antibody of claim 1, wherein A is selected from the group consisting of
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`utomilumab, urelumab, ipilimumab, tremelimumab, pembrolizumab, nivolumab, and atezolizumab.
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`42. The modified antibody of claim 41, wherein A is utomilumab.
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`43. The modified antibody of claim 41, wherein A is urelumab.
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`44. The modified antibody of claim 41, wherein A is ipilimumab.
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`45. The modified antibody of claim 41, wherein A is tremelimumab.
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`46. The modified antibody of claim 41, wherein A is pembrolizumab.
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`47. The modified antibody of claim 41, wherein A is nivolumab.
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`48. The modified antibody of claim 41, wherein A is atezolizumab.
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`49. The modified antibody of claim 1, wherein P comprises an amino acid sequence selected
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`from the group consisting of Peptide l, Peptide 2, Peptide 5, Peptide 6, Peptide lO, Peptide 13,
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`Peptide 26, Peptide 14, Peptide 15, Peptide 20, Peptide 27, Peptide 21, Peptide 22, Peptide 23,
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`Peptide 28, Peptide 29, Peptide 30, Peptide 31, and Peptide 24.
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`50. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence selected from the group consisting of Peptide 1, Peptide 2, Peptide 5,
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`Peptide 6, Peptide 10, Peptide 13, Peptide 26, Peptide 14, and Peptide 15.
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`51. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 1.
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`52. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 2.
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`53. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 5.
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`54. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 6.
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`55. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 10.
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`56. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 13.
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`57. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 26.
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`58. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 14.
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`59. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence according to Peptide 15.
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`60. The modified antibody of claim 1, wherein the target antigen is CTLA4 and P comprises
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`an amino acid sequence selected from the group consisting of Peptide 10, Peptide 13, Peptide 26,
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`Peptide 14, and Peptide 15.
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`61. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence selected from the group consisting of Peptide 20, Peptide 27, Peptide 21,
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`Peptide 22, Peptide 23, Peptide 28, Peptide 29, Peptide 30, Peptide 31, and Peptide 24.
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`62. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 20.
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`63. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 27.
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`64. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 21.
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`65. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 22.
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`66. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 23.
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`67. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 28.
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`68. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 29.
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`69. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 30.
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`70. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 31.
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`71. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence according to Peptide 24.
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`72. The modified antibody of claim 1, wherein the target antigen is PD-Ll and P comprises
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`an amino acid sequence selected from the group consisting of Peptide 27, Peptide 22, Peptide 23,
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`and Peptide 31.
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`73. The modified antibody of claim 37, wherein A comprises a kappa light chain amino acid
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`sequence according to SEQ ID NO: 68.
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`74. The modified antibody of claim 73, wherein A comprises a heavy chain amino acid
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`sequence according to SEQ ID NO: 70.
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`75. The modified antibody of claim 37, wherein the modified antibody comprises an amino
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`acid sequence according to SEQ ID NO: 69.
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`76. The modified antibody of claim 8, wherein P comprises an amino acid sequence selected
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`from the group consisting of Peptide l, Peptide 2, Peptide 5, Peptide 6, Peptide lO, Peptide l3,
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`Peptide 26, Peptide l4, Peptide 15, Peptide 20, Peptide 21, Peptide 22, Peptide 23, Peptide 3 l, and
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`Peptide 24.
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`77. The modified antibody of claim 1, wherein P comprises a peptide sequence with at least
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`two histidines.
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`78. The modified antibody of claim 77, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide 5, Peptide l3, Peptide 26, Peptide l4, Peptide 15,
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`Peptide 3 l, and Peptide 24.
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`79. The modified antibody of claim 77, wherein P comprises a peptide sequence with at least
`two histidines and at least two cysteines.
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`80. The modified antibody of claim 1, wherein P comprises a peptide sequence with at least
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`two charged amino acid residues wherein the charged amino acid residues are selected from the
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`group consisting of aspartate, glutamate, and histidine.
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`81. The modified antibody of claim 80, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide l, Peptide 2, Peptide 5, Peptide 6, Peptide lO, Peptide
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`l3, Peptide 26, Peptide l4, Peptide 15, Peptide 20, Peptide 27, Peptide 2l, Peptide 22, Peptide 23,
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`Peptide 28, Peptide 29, Peptide 30, Peptide 3 l, and Peptide 24.
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`82. The modified antibody of claim 1, wherein P comprises a peptide sequence with at least
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`three charged amino acid residues wherein the charged amino acid residues are selected from the
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`group consisting of aspartate, glutamate, and histidine.
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`83. The modified antibody of claim 81, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide 1, Peptide 2, Peptide 5, Peptide 10, Peptide 13, Peptide
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`26, Peptide 14, Peptide 15, Peptide 21, Peptide 23, Peptide 28, Peptide 31, and Peptide 24.
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`84. The modified antibody of claim 82, wherein P comprises a peptide sequence with at least
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`one histidine and at least two aspartates.
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`85. The modified antibody of claim 1, wherein P comprises a peptide sequence with at least
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`one cysteine.
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`86. The modified antibody of claim 85, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide 5, Peptide 6, Peptide 10, Peptide 13, Peptide 26,
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`Peptide 14, Peptide 15, Peptide 22, Peptide 23, Peptide 29, Peptide 30, Peptide 31, and Peptide 24.
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`87. The modified antibody of claim 1, wherein P comprises a peptide sequence with at least
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`two cysteine amino acid residues.
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`88. The modified antibody of claim 87, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide 6, Peptide 10, Peptide 13, Peptide 26, Peptide 14,
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`Peptide 22, Peptide 23, Peptide 29, Peptide 30, Peptide 31, and Peptide 24.
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`89. The modified antibody of claim 87, wherein P comprises a peptide sequence with at least
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`two cysteines and at least three charged amino acid residues wherein the charged amino acid
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`residues are selected from the group consisting of aspartate, glutamate, and histidine.
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`90. The modified antibody of claim 1, wherein P comprises an amino acid sequence of
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`formula GGX, wherein X is cysteine, alanine, proline, methionine, histidine, or leucine.
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`91. The modified antibody of claim 90, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide 5, Peptide 6, Peptide 10, Peptide 13, Peptide 26,
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`Peptide 14, Peptide 15, Peptide 22, Peptide 23, Peptide 29, Peptide 31, and Peptide 24.
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`92. The modified antibody of claim 1, wherein P comprises an amino acid sequence of GGC.
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`93. The modified antibody of claim 92, wherein P comprises an amino acid sequence
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`selected from the group consisting of Peptide 5, Peptide 6, Peptide 13, Peptide 26, Peptide 14,
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`Peptide 31, and Peptide 24.
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`94. The modified antibody of claim 1, wherein P does not comprise a lysine or arginine.
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`95. The modified antibody of claim 1, wherein P comprises at least one histidine and at least
`
`one aspartate.
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`96. The modified antibody of claim 1, wherein P comprises at least one histidine and at least
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`one glutamate.
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`97. The modified antibody of claim 1, wherein P comprises at least one histidine and at least
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`two glutamates.
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`98. The modified antibody of claim 1, wherein P comprises at least two histidines and at least
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`one aspartate or at least one glutamate.
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`99. The modified antibody of claim 1, wherein P comprises at least one histidine, wherein at
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`least one hydrogen bonding amino acid residue is within two amino acid positions to the histidine,
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`wherein the hydrogen bonding amino acid residue is selected from the group consisting of serine,
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`threonine, tyrosine, asparagine, and glutamine.
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`100.
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`The modified antibody of claim 99, wherein the hydrogen bonding amino acid
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`residue is within one amino acid position to the histidine.
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`101.
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`The modified antibody of claim 99, wherein the hydrogen bonding amino acid
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`residue is serine.
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`102.
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`The modified antibody of claim 99, wherein the hydrogen bonding amino acid
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`residue is threonine.
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`103.
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`The modified antibody of claim 99, wherein the hydrogen bonding amino acid
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`residue is tyrosine.
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`104.
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`The modified antibody of claim 99, wherein the hydrogen bonding amino acid
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`residue is asparagine.
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`105.
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`The modified antibody of claim 99, wherein the hydrogen bonding amino acid
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`residue is glutamine.
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`106.
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`The modified antibody of claim 1, wherein A-L-P does not comprise a protease
`
`cleavage site that releases A from P in a tumor microenVironment.
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`107.
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`The modified antibody of claim1, wherein L comprises a peptide sequence with at
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`least one histidine.
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`108.
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`The modified antibody of claim 107, wherein at acidic pH L is reversibly bound to P.
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`109.
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`The modified antibody of claim 108, wherein P comprises a peptide sequence with at
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`least one aspartic acid or glutamic acid, or a combination thereof.
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`110.
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`The modified antibody of claim 109, wherein the histidine of L forms an interaction
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`with the aspartic acid or glutamic acid of P.
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`111. A pharmaceutical composition, comprising:
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`(a) a modified antibody according to any one of claims 1-110, and
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`(b) a pharmaceutically acceptable excipient.
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