B7-H3 miniproteins, conjugates, and uses thereof
Provided herein are B7-H3-binding miniproteins, conjugates, and uses thereof. B7-H3 binding peptides and conjugates, including radionuclide conjugates, as well as one or more additional proteins such as a decoy peptide are disclosed herein. Such peptides, conjugates, and/or decoys can be used in compositions and methods of treating, diagnosing, monitoring, and/or imaging a disease, disorder, or condition associated with expression of one or more targets (e.g., B7-H3).
1 . A composition comprising a polypeptide having an amino acid sequence comprising SEQ ID NO: 267.
2 . The composition of claim 1 , wherein the polypeptide is a miniprotein (M) that further comprises a chelator (C) conjugated to the N-terminus of (M) through a linker (L).
3 . The composition of claim 2 , further comprising a radionuclide (R) chelated to (C).
4 . The composition of claim 2 , wherein (L) is selected from the group consisting of a polyethylene glycol (PEG) linker of PEG4, PEG, PEG2, PEG6, PEG8, PEG12, PEG24, PEG36, or lys (MPB)-PEG4, an ester linker, an amide linker, a maleimide linker, a succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker, a propanoic acid linker, a dTyr-Gly-Phe (yGF) linker, a caproleic acid linker, or (Gly) n-(gGlu) n, wherein n is from 0 to 10, (Gly) 1-10, and any combination via covalent bond thereof.
5 . The composition of claim 2 , wherein (C) is selected from the group consisting of DOTA, Crown, NOPO, Macropa, lead specific chelator (PSC), N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB), and N-succinimidyl 3-trimethylstannylbenzoate (MeSTB).
6 . The composition of claim 3 , wherein R is selected from the group consisting of Ac-225, Cu-64, Ga-68, Lu-177, Pb-212, In-111, Cu-67, La-132, La-135, Ce-134, F-18, I-131, I-124, Pb-203, Bi-123, Sm-153, Ra-225, and At-211.
7 . The composition of claim 2 , wherein L is PEG4.
8 . The composition of claim 2 , wherein C is DOTA.
9 . The composition of claim 3 , wherein R is Ac-225 or Cu-64.
10 . The composition of claim 6 , wherein L is PEG4, C is DOTA, and R is Ac-225.
11 . The composition of claim 6 , wherein L is PEG4, C is DOTA, and R is Cu-64.
12 . A composition comprising a polypeptide having an amino acid sequence comprising SEQ ID NO: 267, wherein the polypeptide is a miniprotein (M) that further comprises a radionuclide (R) chelated to a chelator (C), which chelator is conjugated to the N-terminus of (M) through a linker (L), wherein R is Ac-225, C is DOTA, and L is PEG4.
13 . A composition comprising a polypeptide having an amino acid sequence comprising SEQ ID NO: 267, wherein the polypeptide is a miniprotein (M) that further comprises a radionuclide (R) chelated to a chelator (C), which chelator is conjugated to the N-terminus of (M) through a linker (L), wherein R is Cu-64, C is DOTA, and L is PEG4.
14 . A method of treating cancer, the method comprising administering the composition of claim 6 to a subject in need thereof.
15 . The method of claim 14 , wherein the administering is intravenous or subcutaneous.
16 . The method of claim 14 , wherein the cancer is selected from prostate cancer, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, melanoma, pancreatic cancer, peripheral neuroma, glioblastoma, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, urothelial cancer, bladder cancer, meningioma, glioma, astrocytoma, cervical cancer, chronic myeloproliferative disorders, colon cancer, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extracranial germ cell tumors, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gestational trophoblastic tumors, hairy cell leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, hypopharyngeal cancer, islet cell carcinoma, Kaposi sarcoma, laryngeal cancer, leukemia, lip cancer, oral cavity cancer, liver cancer, male breast cancer, malignant mesothelioma, medulloblastoma, Merkel cell carcinoma, metastatic squamous neck cell carcinoma, multiple myeloma, plasma cell neoplasms, mycosis fungoides Sezary syndrome, myelodysplastic syndromes, nasopharyngeal cancer, neuroblastoma, head and neck cancer, skin cancer, oropharyngeal cancer, bone cancers, osteosarcoma, malignant fibrous histiocytoma of bone, paranasal sinus cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumors, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, small intestine cancer, soft tissue sarcoma, supratentorial primitive neuroectodermal tumors, pineoblastoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.
17 . The method of claim 16 , wherein the cancer is metastatic.
18 . A method of treating cancer, the method comprising administering to a subject in need thereof a composition comprising a polypeptide having an amino acid sequence comprising SEQ ID NO: 267 and further comprising a chelator (C) conjugated to the N-terminus of (M) through a linker (L), and a radionuclide (R) chelated to (C), wherein (L) is selected from the group consisting of a polyethylene glycol (PEG) linker of PEG4, PEG, PEG2, PEG6, PEG8, PEG12, PEG24, PEG36, or lys (MPB)-PEG4, an ester linker, an amide linker, a maleimide linker, a succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker, a propanoic acid linker, a dTyr-Gly-Phe (yGF) linker, a caproleic acid linker, or (Gly) n-(gGlu) n-, wherein n is from 0 to 10, (Gly) l-10, and any combination via covalent bond thereof, (C) is selected from the group consisting of DOTA, Crown, NOPO, Macropa, lead specific chelator (PSC), N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB), and N-succinimidyl 3-trimethylstannylbenzoate (MeSTB), and (R) is selected from the group consisting of Ac-225, Cu-64, Ga-68, Lu-177, Pb-212, In-111, Cu-67, La-132, La-135, Ce-134, F-18, I-131, 1-124, Pb-203, Bi-123, Sm-153, Ra-225, and At-211.
19 . The method of claim 18 , wherein (R) is selected from the group consisting of Ac-225, Lu-177, Pb-212, Cu-67, and I-131.
20 . The method of claim 18 , wherein (R) is selected from the group consisting of Cu-64, Ga-68, In-111, Pb-203, I-123, I-124, La-132, Ac-225, Lu-177, and F-18.
21 . The method of claim 20 , wherein the composition is a first composition and imaging is performed on the subject after the administration of the first composition.
22 . The method of claim 21 , wherein the subject is further administered a second composition after administration of the first composition, wherein the second composition comprises a polypeptide having an amino acid sequence comprising SEQ ID NO: 267 and further comprising a chelator (C) conjugated to the N-terminus of (M) through a linker (L), and a radionuclide (R) chelated to (C), wherein (L) is selected from the group consisting of a polyethylene glycol (PEG) linker of PEG4, PEG, PEG2, PEG6, PEG8, PEG12, PEG24, PEG36, or lys (MPB)-PEG4, an ester linker, an amide linker, a maleimide linker, a succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker, a propanoic acid linker, a dTyr-Gly-Phe (yGF) linker, a caproleic acid linker, or (Gly) n-(gGlu) n-, wherein n is from 0 to 10, (Gly) 1-10, and any combination via covalent bond thereof, (C) is selected from the group consisting of DOTA, Crown, NOPO, Macropa, lead specific chelator (PSC), N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB), and N-succinimidyl 3-trimethylstannylbenzoate (MeSTB), and R is selected from the group consisting of Ac-225, Lu-177, Pb-212, Cu-67, and I-131.
23 . The method of claim 21 , wherein the first composition comprises an (L) of PEG4, a (C) of DOTA, and an (R) of Cu-64.
24 . The method of claim 22 , wherein the second composition comprises an (L) of PEG4, a (C) of DOTA, and an (R) of Ac-225.