MULTI-PARATOPIC ANTI-PD-1 ANTIBODIES AND USES THEREOF

1 - 50 . (canceled)

51 . A protein comprising a first binding domain, a second binding domain, a third binding domain, and a fourth binding domain, wherein each said binding domain binds to PD-1, wherein at least one of the binding domains comprises a first heavy chain variable region comprising a first CDR of SEQ ID NO: 267, a second CDR of SEQ ID NO: 229, and a third CDR of SEQ ID NO: 230; and a first light chain variable region comprising a first CDR of SEQ ID NO: 174, a second CDR of SEQ ID NO: 227, and a third CDR of SEQ ID NO: 176.

52 . The protein of claim 51 , wherein said first heavy chain variable region comprises the sequence of SEQ ID NO: 257, and wherein said first light chain variable region comprises the sequence of SEQ ID NO: 170.

53 . The protein of claim 51 , wherein only two of the binding domains comprise said first heavy chain variable region and said first light chain variable region.

54 . The protein of claim 51 , wherein the protein is a PD-1 agonist.

55 . The protein of claim 51 , wherein the first binding domain and the second binding domain are in a Fab format.

56 . The protein of claim 55 , wherein the third binding domain and the fourth binding domain are in an scFv format.

57 . The protein of claim 51 , wherein at least one of the other binding domains comprises

a second heavy chain variable region comprising a first CDR of SEQ ID NO: 238, a second CDR of SEQ ID NO: 239, and a third CDR of SEQ ID NO: 240; and a second light chain variable region comprising a first CDR of SEQ ID NO: 40, a second CDR of SEQ ID NO: 237, and a third CDR of SEQ ID NO: 41;

a second heavy chain variable region comprising a first CDR of SEQ ID NO: 238, a second CDR of SEQ ID NO: 264, and a third CDR of SEQ ID NO: 240; and a second light chain variable region comprising a first CDR of SEQ ID NO: 40, a second CDR of SEQ ID NO: 237, and a third CDR of SEQ ID NO: 41; or

a second heavy chain variable region comprising a first CDR having the residues SYYMH, a second CDR of SEQ ID NO: 239, and a third CDR of SEQ ID NO: 240; and a second light chain variable region comprising a first CDR of SEQ ID NO: 276, a second CDR of SEQ ID NO: 237, and a third CDR of SEQ ID NO: 41.

58 . The protein of claim 57 , wherein

said second heavy chain variable region comprises the sequence of SEQ ID NO: 262, and wherein said second light chain variable region comprises the sequence of SEQ ID NO: 261;

said second heavy chain variable region comprises the sequence of SEQ ID NO: 202, and wherein said second light chain variable region comprises the sequence of SEQ ID NO: 36;

said second heavy chain variable region comprises the sequence of SEQ ID NO: 275, and wherein said second light chain variable region comprises the sequence of SEQ ID NO: 36; or

said second heavy chain variable region comprises the sequence of SEQ ID NO: 256, and wherein said second light chain variable region comprises the sequence of SEQ ID NO: 259.

59 . The protein of claim 57 , wherein two of the binding domains comprise said second heavy chain variable region and said second light chain variable region.

60 . The protein of claim 51 , comprising a first polypeptide chain and a second polypeptide chain, wherein:

the first polypeptide chain has a formula of from N-terminus to C-terminus:

[VH-A]-[CH1]-[CH2]-[CH3]-[Linker 1]-[VH-B]-[Linker 2]-[VK-B]; or

[VH-A]-[CH1]-[CH2]-[CH3]-[Linker 1]-[VK-B]-[Linker 2]-[VH-B]; and

the second polypeptide chain has a formula of from N-terminus to C-terminus:

[VK-A]-[CK]; or

the first polypeptide chain has a formula of from N-terminus to C-terminus:

[VH-B]-[CH1]-[CH2]-[CH3]-[Linker 1]-[VH-A]-[Linker 2]-[VK-A]; or

[VH-B]-[CH1]-[CH2]-[CH3]-[Linker 1]-[VK-A]-[Linker 2]-[VH-A]; and

the second polypeptide chain has a formula of from N-terminus to C-terminus:

[VK-B]-[CK],

wherein:

VH-A is the first heavy chain variable region;

VK-A is the first light chain variable region;

VH-B is the second heavy chain variable region;

VK-B is the second light chain variable region;

CH1 is a constant heavy domain 1 of human IgG1;

CH2 is a constant heavy domain 2 of human IgG1;

CH3 is a constant heavy domain 3 of human IgG1;

CK is a constant domain of kappa light chain;

Linker 1 is a glycine/serine, glycine/alanine, glycine/glutamic acid/serine, or alanine/glutamic acid/lysine linker; and

Linker 2 is a glycine/serine, glycine/alanine, glycine/glutamic acid/serine, or alanine/glutamic acid/lysine linker.

61 . The protein of claim 60 , wherein Linker 1 comprises the sequence of (GGGGS)n (SEQ ID NO: 303), wherein n is 1-4; and wherein Linker 2 comprises the sequence of (GGGGS)n (SEQ ID NO: 303), (GGGSE)n (SEQ ID NO: 305), or (GGGGA)n (SEQ ID NO: 304), wherein each n is independently, 1-4.

62 . The protein of claim 60 , wherein

the first polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 256, 12, 6, 257, 7, and 170; and the second polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 259 and 274;

the first polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 275, 12, 6, 257, 7, and 170; and the second polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 36 and 274;

the first polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 202, 12, 6, 257, 7, and 170; and the second polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 36 and 274; or

the first polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 257, 12, 1, 261, 7, and 262; and the second polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 170 and 274.

63 . A pharmaceutical composition comprising the protein of claim 51 and a pharmaceutically acceptable carrier.

64 . A method of treating an unwanted immune response in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 63 .

65 . The method of claim 64 , wherein the unwanted immune response comprises Systemic Lupus Erythematosus (SLE); Aicardi-Goutieres syndrome; bilateral striatal necrosis; chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE); complete non-penetrance; dyschromatosis symmetrica hereditaria; familial chilblain lupus; Japanese autoinflammatory syndrome with lipodystrophy (JASL); joint contractures, muscle atrophy, microcytic anaemia, panniculitis, and lipodystrophy (JMP); Mendelian susceptibility to mycobacterial disease (MSMD); Nakajo-Nishimura syndrome; retinal vasculopathy with cerebral leukodystrophy (RVCL); spastic paraparesis; STING-associated vasculopathy with onset in infancy (SAVI); Singleton-Merten syndrome; spondylochondromatosis (SPENCD); an autoimmune disorder; inflammatory bowel disease; autoimmune hepatitis; primary sclerosing cholangitis; Type 1 diabetes; a transplant; GVHD; Crohn's disease; or ulcerative colitis.

66 . A protein comprising a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 257, 12, 1, 261, 7, and 262; and the second polypeptide chain comprises from N-terminus to C-terminus the sequences of SEQ ID NO: 170 and 274.

67 . A pharmaceutical composition comprising the protein of claim 66 and a pharmaceutically acceptable carrier.

68 . A method of treating an unwanted immune response in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 67 .

69 . The method of claim 68 , wherein the unwanted immune response comprises Systemic Lupus Erythematosus (SLE); Aicardi-Goutieres syndrome; bilateral striatal necrosis; chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE); complete non-penetrance; dyschromatosis symmetrica hereditaria; familial chilblain lupus; Japanese autoinflammatory syndrome with lipodystrophy (JASL); joint contractures, muscle atrophy, microcytic anaemia, panniculitis, and lipodystrophy (JMP); Mendelian susceptibility to mycobacterial disease (MSMD); Nakajo-Nishimura syndrome; retinal vasculopathy with cerebral leukodystrophy (RVCL); spastic paraparesis; STING-associated vasculopathy with onset in infancy (SAVI); Singleton-Merten syndrome; spondylochondromatosis (SPENCD); an autoimmune disorder; inflammatory bowel disease; autoimmune hepatitis; primary sclerosing cholangitis; Type 1 diabetes; a transplant; GVHD; Crohn's disease; or ulcerative colitis.