WHATIS CLAIMEDIS:
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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 antibodyor antibody fragmentthat 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 and L is bound to A outside an antigen
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`bindingsite.
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`2. The modified antibody of claim 1, wherein at physiological pHPis reversibly bound to A
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`throughionic, 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 any one of claims 1-2, wherein at physiological pHPis
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`reversibly bound to A at or near the antigen bindingsite.
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`4. The modified antibody of any one of claims 1-3, wherein P inhibits the binding of A to
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`the target antigen at physiological pH and P doesnotinhibit the binding ofA to the target antigen at
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`acidic pH.
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`5. The modified antibody of any one of claims 1-4, wherein in tissue other than a tumor
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`microenvironment, P sterically blocks A from bindingto the target antigen.
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`6. The modified antibody of any one of claims 1-5, wherein at a tumor microenvironment, P
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`is removed from the antigen binding site, and the antigen bindingsite of A is exposed.
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`7. The modified antibody of any one of claims 1-6, wherein the modified antibody has an
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`increased binding affinity for the target antigen in a tumor microenvironment compared to the
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`binding affinity of the modified antibody for the target antigen in a non-tumor microenvironment.
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`8. The modified antibody of any one of claims 1-7, wherein P comprises a peptide sequence
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`with at least 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 any one of claims 1-9, wherein at acidic pHPis reversibly
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`boundto A in a region of A that is not the antigen bindingsite.
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`11. The modified antibody of claim 10, wherein at acidic pH P is reversibly bound to A ina
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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 any one of claims 1-11, wherein P is resistant to cleavage by a
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`protease.
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`13. The modified antibody of any one of claims 1-12, wherein physiological pH is about pH
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`7.4.
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`14. The modified antibody of any one of claims 1-12, wherein acidic pH is about pH 6.0 to
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`about pH 7.0.
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`15. The modified antibody of any one of claims 1-14, wherein P comprises a peptide
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`sequence ofat least 6 amino acidsin length.
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`16. The modified antibody of any one of claims 1-15, wherein P comprises a peptide
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`sequence ofat least 10 amino acidsin length.
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`17. The modified antibody of any one of claims 1-16, wherein P comprises a peptide
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`sequence ofat least 6 to 20 amino acids in length.
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`18. The modified antibody any one of claims 1-17, wherein P comprises a modified amino
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`acid, a non-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 boundto 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 combinationthereof.
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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 any one of claims 1-22, wherein L is a peptide sequence having
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`at least 5 to no more than 50 amino acids.
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`24. The modified antibody of any one of claims 1-19, wherein L has a formula selected from
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`the group consisting of: (GS),, wherein n is an integer from 6 to 20 (SEQ ID NO: 1); (G2S)n,
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`wherein n is an integer from 4 to 13 (SEQ ID NO: 2); (G3S)n, wherein n is an integer from 3 to 10
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`(SEQ ID NO: 3); and (G4S)n, wherein n is an integer from 2 to 8 (SEQ ID NO: 4); and (G),, wherein
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`n is an integer from 12 to 40 (SEQ ID NO: 5).
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`25. The modified antibody of any one of claims 1-23, wherein L has a formula comprising
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`(GGSGGD),, wherein n is an integer from 2 to 6 (SEQ ID NO: 8).
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`26. The modified antibody of any one of claims 1-23, wherein L has a formula comprising
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`(GGSGGE),, wherein n is an integer from 2 to 6 (SEQ ID NO: 9).
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`27. The modified antibody of any one of claims 1-20, wherein L has a formula comprising
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`(GGGSGSGGGGS) », wherein n is an integer from 1 to 3 (SEQ ID NO: 6).
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`28. The modified antibody of any one of claims 1-20, wherein L has a formula comprising
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`(GGGGGPGGGGP) », wherein n is an integer from 1 to 3 (SEQ ID NO: 7).
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`29. The modified antibody of any one of claims 1-21, wherein L has a formula selected from
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`(GX), wherein X is serine, aspartic acid, glutamic acid, threonine, or proline and n isat least 20
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`(SEQ ID NO: 24); (GGX),, wherein X is serine, aspartic acid, glutamic acid, threonine, or proline
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`andnis at least 13 (SEQ ID NO: 25); (GGGX),, wherein X is serine, aspartic acid, glutamic acid,
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`threonine, or proline andnis at least 10 (SEQ ID NO: 26); (GGGGX),, wherein X is serine, aspartic
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`acid, glutamic acid, threonine, or proline and n is at least 8 (SEQ ID NO: 27); (G;X)n, wherein X is
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`serine, aspartic acid, glutamic acid, threonine, or proline and n isat least 15, and z is between 1 and
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`20 (SEQ ID NO: 28).
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`.
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`30. The modified antibody of any one of claims 1-29, whereinLis resistant to cleavage by a
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`protease.
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`31. The modified antibody of any one of claims 1-30, wherein L comprises a modified amino
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`acid.
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`32. The modified antibody of claim 31, wherein the modified amino acid comprises a post-
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`translational modification.
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`33. The modified antibody of any one of claims 1-32, wherein L comprises a non-natural
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`amino acid or a 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 any one of claims 1-34, wherein the target antigen is selected
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`from the group consisting of: 4-1BB, CTLA4, and PD-1.
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`36. The modified antibody of any one of claims 1-35, wherein the target antigen is 4-1BB.
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`37. The modified antibody of any one of claims 1-35, wherein the target antigen is CTLA4.
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`38. The modified antibody of any one of claims 1-35, wherein the target antigen is PD-1.
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`39. The modified antibody of any one of claims 1-38, wherein A is a full length antibody, a
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`single-chain antibody, an Fab fragment, an Fab’ fragment, an (Fab’)2 fragment, an Fv fragment, a
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`divalent single chain antibody, bispecific antibody, a trispecific antibody, a tetraspecific antibody, or
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`an antibody drug conjugate.
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`40. The modified antibody of any one of claims 1-39, wherein A is selected from the group
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`consisting of utomilumab, urelumab, ipilimumab, tremelimumab, pembrolizumab, and nivolumab.
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`41. The modified antibody of any one of claims 1-40, wherein A is utomilumab.
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`42. The modified antibody of any one of claims 1-40, wherein A is urelumab.
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`43. The modified antibody of any one of claims 1-40, wherein A is ipilimumab.
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`44. The modified antibody of any one of claims 1-40, wherein A is tremelimumab.
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`45. The modified antibody of any one of claims 1-40, wherein A is pembrolizumab.
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`46. The modified antibody of any one of claims 1-40, wherein A is nivolumab.
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`47. A pharmaceutical composition, comprising:
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`(a) a modified antibody according to any one of claims 1-46; and
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`(b) a pharmaceutically acceptable excipient.
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