Radiopharmaceutical compositions targeting glypican-3 and uses thereof

Abstract

Provided herein are radiopharmaceuticals and conjugates, and compositions thereof, targeting glypican-3 (GPC3), and uses thereof. In one aspect, provided herein are conjugates that comprise a peptide with avidity to GPC3 and a metal chelator configured to bind with a radionuclide. The conjugates described herein can further comprise a linker connecting the chelator and the peptide. The conjugates described herein can further comprise a radionuclide. In one aspect, provided herein are radiopharmaceuticals that comprise a peptide and a metal chelator bound to a radionuclide. The conjugates described herein can further comprise a linker connecting the chelator and the peptide. Further provided herein are methods of treating cancer by administering the described radiopharmaceuticals, conjugates, compositions thereof.

Description

Attorney Docket No. 01277-0089-00PCT-RYZ RADIOPHARMACEUTICAL COMPOSITIONS TARGETING GLYPICAN-3 AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 730,580, filed on December 11, 2024, which is incorporated herein by reference in its entirety for any purpose.JOINT RESEARCH AGREEMENT

[0002] Subject matter disclosed herein was developed, and the claimed invention was made by, or on behalf of, one or more parties to a Joint Research Agreement (JRA), within the meaning of 35 U. S. C. § 100(h) and 37 C. F. R. § 1.9(e), that was in effect on or before the effective filing date of the claimed invention. Said one or more parties to the JRA consist of PeptiDream, Inc. (Kanagawa, Japan) and RayzeBio, Inc. (San Diego, CA, U. S. A.). The claimed invention was made as a result of activities undertaken within the scope of said Joint Research Agreement.SEQUENCE LISTING

[0003] This application contains a Sequence Listing, which has been submitted electronically in.xml format as part of the specification and is incorporated herein by reference in its entirety. Said XML file, created on November 5, 2025, is named “01277-0089-00PCT-RYZ SL.xml,” and is 1,770,498 bytes in size.TECHNICAL FIELD

[0004] The present disclosure relates to conjugates comprising peptides that bind to glypican-3 (GPC3) and to compositions comprising such conjugates and uses thereof. In an aspect, the present disclosure relates to the use of said conjugates in preventing, suppressing or treating a disease or disorder characterized by overexpression or decreased expression of GPC3 in diseased tissue, such as in a tumor where GPC3 is overexpressed.BACKGROUND

[0005] Glypican-3 (GPC3) is a heparan sulfate (HS) glycoprotein, belonging to the sulfate heparan proteoglycan family, and which is anchored on the cell membrane surface by phosphatidylinositol (GPI) anchor. The GPC3 core protein comprises 580 amino acids, with a molecular weight of about 70 kDa. It is cut by furin (Furin), generating a 40 kDa N-terminal subunit and a 30 kDa C -terminal subunit, connected to each other by a disulfide bond. GPC3’s two HS side chain is combined at the position close to the C end (Takahiro Nishida, Hiroaki Kataoka. Glypican 3 -Targeted Therapy in Hepatocellular Carcinoma, Cancer 2019; 11 (9): 1339).

[0006] GPC3 can play an important role in the cell proliferation of embryo layer tissue. Deletion of GPC3 gene can cause excessive growth syndrome, namely Simpson-Golabi-Behmel syndrome (SGBS). GPC3 can be clearly expressed throughout the entire fetal stage, and after birth to adult stage, except for placental, breast, mesodermal, ovarian, lung and kidney tissue with weak expression, other normal tissues have no obvious expression.

[0007] Abnormal GPC3 expression has been found in multiple tumour tissues of adult, such asAttorney Docket No. 01277-0089-00PCT-RYZ hepatocellular carcinoma (HCC), lung squamous carcinoma, gastric cancer, ovarian cancer and so on. Especially highly expressed in HCC cells, GPC3 improves autocrine / paracrine canonical Wnt signal transmission, and promotes growth and invasion of HCC cells (Capurro MI, Xiang Y-Y, Lobe C, Filmus J. Glypican-3 promotes the growth of hepatocellular carcinoma by -stimulating canonical Wnt signaling; Cancer Res 2005, 65(14): 6245-54.). Immunohistochemical staining detection shows that about 70% of HCC patient tumor tissue exhibits high GPC3 protein expression (Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma;Gastroenterology 2003, 125(1 ): 89-97). Thus, GPC3 is considered as a candidate target for tumor treatment.

[0008] Codrituzumab (also known as GC33 antibody) is a recombinant humanized monoclonal antibody developed in Japan by Chugai Pharmaceutical Co., which binds to the region of GPC3 protein proximal membrane end. GC33 antibody targets GPC3 positive HCC cells, and can generate antibody dependent cell toxicity (ADCC). In phase I clinical trials, Codrituzumab shows good immune tolerance. The HCC patient can generate an anti-tumour effect (Ikeda M, Ohkawa S, Okusaka T, et al. Japanese phase I study of GC33, a-antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sei.2014, 105, 455-462). However, in the phase II clinical trial with 185 late-stage liver cancer patients, the therapeutic efficacy of Codrituzumab was not impressive compared with the control group.

[0009] Therefore, novel GPC3-binding peptides and compositions comprising the GPC3-binding peptide are both useful and desired,SUMMARY

[0010] Provided herein is a conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising:(a) a peptide of Formula I:\JL / ’z. XsFormula I,wherein:R is -CH2-CO-; and(i) Xi is MeLys, MeLysAc, MeAla, MeGlu, MeGln, or CrpG, wherein the N-terminal nitrogen of Xi is attached to the C(O) of R; andX2 is Melle, MeGln, MeLys, MeHseMe, MeLysCOpipzaa, or MeGlu; and X3is Asp, MeAsp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andX4 is Miglin, MeLys, MeAspapCOpipzaa, MeGlu, or CrpG; andAttorney Docket No. 01277-0089-00PCT-RYZ X5is F4C00, MeF4C00, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andX6 is TMe, altMe, Ile, or Leu; andX7 is TMe, Ile, Val, Leu, Gcpe, or Eva; andX8is Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; andX9is MeNal27N, MeF3Me4C, MeF34dOMe, or MeW7N; andX;o is Gly, MeGly, D-AIa, D-Ser, or D-Pro; andX;i is 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; andX12 is MeCys or Cys, wherein sulfur of the X12 side chain is covalently attached to R, ~ CK, NHO y2N N H2and carboxylic acid of X12 is replaced with -C(0)NIl2 orH • and wherein X-;is MeGlu or CrpG; or X2 is MeLys; or X3 is MeAsp, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or X4is MeGlu, or CrpG; or X is MeF4C00, 4Py, 3Py6NH2, 3Py 6COO, F4(SO3H), or (PyrrCOO)A; or Xe is alTMe or Leu; or X? is TMe, Vai, Leu, Gcpe, or Eva; or X8is Cha, F3OII, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or Xg is MeF3Me4C, MeF34dOMe, or MeW7N; or X10 is MeGly, D-Ala, D-Ser, or D-Pro; orXn is 3Py6Pyrazoll, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; or X is Cys; or(ii) Xi to Xj2 have a sequence from Table 1, 2, 3, 4, 9A, or 20A (and, in some aspects, from Table 1, 2, 3, 4, or 9A); and(b) a metal chelator covalently attached to the peptide.

[0011] Also provided herein is a conjugate or pharmaceutically acceptable salt thereof, the conjugate comprising:(a) a peptide of Formula 11:Attorney Docket No. 01277-0089-00PCT-RYZFormula IIwherein:R* is -CH2-S-CH2-CO-;each Z is independently selected from H and Me; ando. NH2NNH2Qis -NIL or H; and(i) Ai is the side chain of Lys, LysAc, Ala, Glu, Gin, or CrpG; andA2is the side chain of lie, Gin, Lys, HseMe, LysCOpipzaa, or Glu; and As is the side chain of Asp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andA4 is the side chain of Gin, Lys, AspapCOpipzaa, Glu, or CrpG; andAs is the side chain of F4COO, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andAs is the side chain of TMe, altMe, He, or Leu; andA? is the side chain of Tme, He, Vai, Leu, Gcpe, or Eva; andA« is the side chain of Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; and A9 is the side chain of Nal27N, F3Me4C, F34dOMe, or W7N; andAjo is the side chain of Gly, D-Ala, D-Ser, or D-Pro; andAn is the side chain of 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4pip lAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C;and wherein Ai is the side chain of Glu or CrpG; or A2is the side chain of Lys; or As is the side chain of Asp, Ser, Thr, Ala, or Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or A4 is the side chain of Glu or CrpG; or A 5 is the side chain of F4COO, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; or AgAttorney Docket No. 01277-0089-00PCT-RYZ is the side chain of alTMe or Leu; or A? is the side chain of Tme, Vai, Leu, Gcpe, or Eva; or As is the side chain of Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or Ao is the side chain of F3Me4C, MeF34dOMe, or MeW7N; or Aio is the side chain of Gly, D-Ala, D-Ser, or D-Pro; or Ai i is the side chain of 3Py6Pyrazol 1, 3Py6O4pip IMs, 3Py6O4pip 1 Ac, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; or (ii) Ai to An correspond to the side chains of X;to Xu of a sequence from Table 1, 2, 3, 4, 9A, or 20A (and, in some aspects, from Table 1, 2, 3, 4, or 9A); and(b) a metal chelator covalently attached to the peptide.

[0012] In some embodiments, X;to Xi2of the peptide of Formula (I) have a sequence from Table 1, 2, 3, 4, 9A, or 20A. In some embodiments, Xi to Xi2of the peptide of Formula (I) have a sequence from Table 1, 2, 3, 4, or 9A. In some embodiments, Xi to X!2of the peptide of Formula (I) have the sequence of SEQ ID NO: 226, 520, or 521. In some embodiments, Xi to Xi2of the peptide of Formula (I) have the sequence of SEQ ID NO: 226. in some embodiments, X;to X12of the peptide of Formula (I) have the sequence of SEQ ID NO: 520. In some embodiments, Xi to XJ2of the peptide of Formula (I) have the sequence of SEQ ID NO: 521,

[0013] In some embodiments, the conjugate is a conjugate from Table 5, 6, 7, 8, 9B, or 20B. In some embodiments, the conjugate is a conjugate from Table 5, 6, 7, 8, or 9B. In some embodiments, the conjugate or pharmaceutically acceptable salt thereof is C-226-DOTA, C-226-NOTA, C-520, or C-521. In some embodiments, the conjugate or pharmaceutically acceptable salt thereof is C-226-DOTA or C-226-NOTA. In some embodiments, the conjugate or pharmaceutically acceptable salt thereof is C-520. In some embodiments, the conjugate or pharmaceutically acceptable salt thereof is C-521.

[0014] in some embodiments, the metal chelator is covalently attached to the side chain of the first amino acid of the peptide (Xi, Ai), the side chain of the second amino acid of the peptide (X2, A2), the side chain of the third amino acid of the peptide (X2, A?,), the side chain of the fourth amino acid of the peptide (X4, A4), the side chain of the eighth amino acid of the peptide (X8, As), or to the C-terminus of the C -terminal amino acid of the peptide (Xi2, Q, when Q is -NH2); or wherein the peptide comprises a thirteenth amino acid and the metal chelator is covalently attached to the side chain of the thirteenth amino acid (Xn, Q, when Q is D-Lys).

[0015] In some embodiments, the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn- SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN- Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-IIEIIA, H2-MACROPA-NCS, Hl-MACROPA, II2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA.Attorney Docket No. 01277-0089-00PCT-RYZ in some embodiments, the metal chelator is:(DOTA),Attorney Docket No. 01277-0089-00PCT-RYZsome embodiments, the metal chelator isometal chelator is 0(NOTA)

[0016] In some embodiments, the conjugate or pharmaceutically acceptable salt thereof further comprises a linker that covalently connects the peptide to the metal chelator. In some embodiments, the linker comprises 3 to 10 intervening non -hydrogen, organic atoms between the metal chelator and the peptide.

[0017] In some embodiments, the conjugate or pharmaceutically acceptable salt thereof is directly attached to the metal chelator.

[0018] Also provided herein is a conjugate or pharmaceutically acceptable salt thereof having the following structure (SEQ ID NO: 591):O=(OH wherein XMIS a radionuclide.

[0019] Also provided herein is a conjugate or pharmaceutically acceptable salt thereof having the following structure (SEQ ID NO: 592):Attorney Docket No. 01277-0089-00PCT-RYZwherein XM is a radionuclide.

[0020] Also provided herein is a conjugate or pharmaceutically acceptable salt thereof havingAttorney Docket No. 01277-0089-00PCT-RYZ wherein Xxiis a radionuclide.

[0021] Also provided herein is a conjugate or pharmaceutically acceptable salt thereof havingwherein XMis a radionuclide.

[0022] In some embodiments, the conjugate or pharmaceutically acceptable salt thereof comprises a radionuclide bound to the metal chelator. In some embodiments, the radionuclide is an alpha particleemitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is Ac -225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213. In some embodiments, the alpha particle-emitting radionuclide is Ac-225. In some embodiments, the radionuclide is a beta particle¬ emitting radionuclide. In some embodiments, the beta particle-emitting radionuclide is Cu-67, Lu-177, ¥-90, Rli-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111. In some embodiments, the beta particle -emitting radionuclide is Lu-177. In some embodiments, the radionuclide is a positron-emitting radionuclide. In some embodiments, the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152. In some embodiments, the positron-emitting radionuclide is Ga-68.

[0023] In some embodiments, the peptide is not a peptide from Table A. In some embodiments, the peptide does not have a sequence of any of SEQ ID Nos: 1-72. In some embodiments, the conjugate is not a conjugate from Table B.

[0024] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a conjugate, or a pharmaceutically acceptable salt thereof, as described herein, and a pharmaceutically acceptable excipient or carrier. In one aspect, the present disclosure relates to a pharmaceuticalAttorney Docket No. 01277-0089-00PCT-RYZ composition comprising a radiopharmaceutical or pharmaceutically acceptable salt thereof, as described herein, and a pharmaceutically acceptable excipient or carrier.

[0025] In one aspect, the present disclosure relates to a method of treating a disease or disorder characterized by overexpression of glypican 3 (GPC3) in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a radiopharmaceutical or pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition as described herein. In one aspect, the present disclosure relates to a method of treating a disease or disorder characterized by overexpression of GPC3 in a subject in need of treatment, the method comprising: administering to the subject a first radiopharmaceutical or pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of a second radiopharmaceutical or pharmaceutically acceptable salt thereof, wherein: the first radiopharmaceutical or pharmaceutically acceptable salt thereof is described herein, and wherein the radionuclide is a diagnostic radionuclide; and the second radiopharmaceutical or pharmaceutically acceptable salt thereof is described herein, and wherein the radionuclide is a therapeutic radionuclide. In one aspect, the present disclosure relates to a method of diagnosing a disease or disorder characterized by overexpression of GPC3 in a subject in need thereof, comprising administering to the subject a radiopharmaceutical or pharmaceutically acceptable salt thereof, or pharmaceutical composition as described herein; and imaging the subject, thereby determining expression level of GPC3 in the subject, wherein the radionuclide is suitable for use as an imaging isotope. In one aspect, the present disclosure relates to a method of treating a disease or disorder characterized by overexpression of GPC3, in a subject in need of treatment, the method comprising administering to the subject the radiopharmaceutical or pharmaceutically acceptable salt thereof as described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, tire cancer is selected from hepatocellular carcinoma, squamous cell carcinoma of the lung, lung adenocarcinoma, germ cell tumors, hepatoblastoma, wilms tumor, malignant rhabdoid tumors, rhabdomyosarcoma, liposarcoma, thyroid cancers, pancreatic cancer, small bowel cancer, small cell neuroendocrine carcinoma (SCNC), hormonally treated, castration resistant prostatic adenocarcinoma, ovarian cancer, gastric cancer, esophageal carcinoma and malignant melanoma.

[0026] In one aspect, the present disclosure relates to a kit, tester, or composition for determining the expression level of GPC3 in a sample, wherein the kit, tester, or composition comprises the radiopharmaceutical or conjugate or pharmaceutically acceptable salt thereof as described herein. In some embodiments, tire kit, tester, or composition is adapted for use in a method of diagnosing a disease or disorder characterized by an overexpression or a decreased expression of GPC3. In some embodiments, the sample is from a subject suspected of having a disease or disorder characterized by an overexpression or a decreased expression of GPC3.

[0027] In one aspect, the present disclosure relates to the use of a radiopharmaceutical, or conjugate, or pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of GPC3.Attorney Docket No. 01277-0089-00PCT-RYZ

[0028] In one aspect, the present disclosure relates to the use of a radiopharmaceutical, or conjugate, or pharmaceutically acceptable salt thereof as described herein for use in diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of GPC3,INCORPORATION BY REFERENCE

[0029] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] All features of embodiments which are described in this disclosure are not mutually exclusive and can be combined with one another. For example, elements of one embodiment can be utilized in the other embodiments without further mention. A detailed description of specific embodiments is provided herein below with reference to the accompanying drawings in which:

[0031] FIG. 1 A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG. IB illustrates the same metal chelators as FIG. 1 A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle-.

[0032] FIG. 2A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG. 2B illustrates the same metal chelators as FIG. 2A, except that a part of tire linker or the peptide covalently connected to the metal chelator is shown in the dashed circle-.

[0033] FIG. 3A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG, 3B illustrates the same metal chelators as FIG. 3 A, except that a part of tire linker or the peptide covalently connected to the metal chelator is shown in the dashed circle' ' -.

[0034] FIG. 4A illustrates exemplary metal chelators of the present disclosure, wherein represents the attachment point of a metal chelator to the remaining conjugate. FIG. 4B illustrates the same metal chelators as FIG. 4 A, except that a part of the l inker or the peptide covalently connected to the metalchelator is shown in the dashed circle1-.

[0035] FIG. 5 illustrates the structures of representative metal chelators.

[0036] FIG. 6 illustrates the structures of representative metal chelators.

[0037] FIG. 7 illustrates the structures of representative metal chelators.

[0038] FIG. 8 illustrates the structures of representative metal chelators.

[0039] FIG. 9 illustrates the structures of representative metal chelators.

[0040] FIG. 10 illustrates the structures of representative metal chelators.

[0041] FIG. 11 illustrates the structures of representative metal chelators.

[0042] FIG. 12 illustrates the structures of representative metal chelators.

[0043] FIG. 13 illustrates the structures of representative metal chelators.Attorney Docket No. 01277-0089-00PCT-RYZ

[0044] FIG. 14 illustrates the structures of representative metal chelators.

[0045] FIG. 15 illustrates the structures of representative metal chelators.

[0046] FIG. 16 illustrates the structures of representative metal chelators,

[0047] FIG. 17 illustrates the structures of representative metal chelators.

[0048] FIG. 18 illustrates the structures of representative metal chelators.

[0049] FIG. 19 illustrates the structures of representative metal chelators.DETAILED DESCRIPTION

[0050] It should be understood that both the general descriptions and the detailed description below are merely illustrative and descriptive and do not limit the present technology of the present application. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope,

[0051] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment,

[0052] The headings used in the present specification are for structural purposes only and must not be construed as limiting the subject matter described.

[0053] In the present specification, the use of the singular form includes the plural form unless otherwise specified. In the present specification, the use of "‘or (or)” means “and / or (and / or)” unless otherwise stated. Furthermore, terms such as “element” or “component” encompass both an element and a component including one unit and an element and a component including two or more subunits unless when otherwise specified.

[0054] The recitation herein of numerical ranges by endpoints is intended to include all numbers subsumed within that range (e.g., a recitation of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 4.32, and 5).

[0055] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0056] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.I. Definitions

[0057] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When rangesAttorney Docket No. 01277-0089-00PCT-RYZ are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0058] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how' tire value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0059] As used herein, the term “conjugate” refers to a peptide described herein that is chelated or bound to, or is capable of being chelated or bound to, a radionuclide. For example, a peptide described herein may be chelated or bound to, or capable of being chelated or bound to, a radionuclide through a metal chelator. A conjugate described herein may, but need not, comprise a radionuclide. In some embodiments, a conjugate described herein does not comprise a radionuclide,

[0060] As used herein, the term “radiopharmaceutical” refers to a conjugate comprising a radionuclide. In some embodiments, the radionuclide is covalently bound to the conjugate, in some embodiments, the radionuclide is bound to the conjugate through a metal chelator.

[0061] The term “comprising” (and related terms such as “compose” or “comprises” or “having” or “including”) are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in oilier certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0062] " Amino" refers to the -NH2radical.

[0063] " Cyano" refers to the -CM radical.

[0064] " Nitro" refers to the -NO2 radical.

[0065] " Oxo" refers to the =0 radical.

[0066] " Imino" refers to the =N-H radical.

[0067] " Oximo" refers to the =N-OH radical.

[0068] " Hydrazino" refers to the =N-NH2 radical.

[0069] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0070] “Hydroxyamino” refers to the -NH-OH radical.

[0071] “Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkyl carbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification,Attorney Docket No. 01277-0089-00PCT-RYZ an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0072] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2 -pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “Cj-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a Ci-Cs, alkyl, a Ci-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -C=CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0073] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH₂-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-In some embodiments, the alkylene is -CH₂-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0074] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1 -propenyl(-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkeny l” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the presentAttorney Docket No. 01277-0089-00PCT-RYZ definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C -C alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C -C alkenyl, a ( -(. alkenyl, a ( -C alkenyl, or a C.- alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0075] The term “alkenylene” or “alkenylene chain” refers to an optionally substituted straight or branched divalent hydrocarbon chain in which at least one carbon -carbon double bond is present linking the rest of the molecule to a radical group. In some embodiments, the alkenylene is -CH=CH-, - CHzCH^CH-, or -CH^CHCHz-. In some embodiments, the alkenylene is CH=CH-. In some embodiments, the alkenylene is ~-CH2CH=CH- In some embodiments, the alkenylene is ~CH=CHCH2-.

[0076] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and tire like. Whenever it appears herein, a numerical range such as '( -C alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated, in some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C₂ alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH₂, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. The term “alkynylene” refers to an optionally substituted straight¬ chain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple -bonds.

[0077] “Alkylamino” refers to a radical of the formula -N(Ra)2 where Rais an alkyl radical as defined, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7 heterocycloalkyl ring. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. InAttorney Docket No. 01277-0089-00PCT-RYZ some embodiments, the alkylamino is optionally substituted with halogen.

[0078] “Alkoxy"’ refers to a radical of the formula -OR.awhere Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0079] “Aminoalky 1” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, tire alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, tire hydroxyalkyl is aminomethyl.

[0080] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical ( / .<?., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl"’) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)₂NH-C₁-C₉alkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, tire aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0081] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups havingAttorney Docket No. 01277-0089-00PCT-RYZ from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetramyl, decalinyl, 3,4-dihydronaphthalenyl-l(2H)-one, spiro[2.2]pentyl, norbomyl and bicycle[l.l.l]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C₃-C₈ fully saturated cycloalkyl or C₃-C₈ cycloalkenyl), from three to six carbon atoms (e.g., C₃-C₆ fully saturated cycloalkyl or C₃-C₅ cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2. I.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalky 1, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - -CF₃, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0082] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0083] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1 -fluoromethyl -2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radicalAttorney Docket No. 01277-0089-00PCT-RYZ is optionally substituted as defined above for an alkyl group.

[0084] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆ heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of tire heteroalkyl. Examples of such heteroalkyl are, for example, -CH2-O-CH₂-, -CH₂-N(alkyl)-CH₂-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, OCH2CH2OCH2CH2O-, or - OCH2CH2OCH2CH2OCH2CH2O-. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0085] As used herein, a “heteroalkylene” refers to divalent heteroalkyl group. Examples of such heteroalkylene are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, - OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0086] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one hetero ring atom, e.g., a heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyI,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C₂-C₁₅ fully saturated heterocycloalkyl or C₂-C₁₅ heterocycloalkenyl), from two to ten carbon atoms (e.g., C₂-C₁₀ fully saturated heterocycloalkyl or C2-Cio heterocycloalkenyl), from two to eight carbon atoms (e.g., C₂-C₈ fully saturated heterocycloalkyl or C2-Cs heterocycloalkenyl), from two to seven carbon atoms (e.g,, C₂-C₇ fully saturated heterocycloalkyl or C₂-C₇ heterocycloalkenyl), from two to six carbon atoms (e.g., C₂-C₆ fully saturated heterocycloalkyl or C₂-C₆ heterocycloalkenyl), from two to five carbon atoms (e.g.,Attorney Docket No. 01277-0089-00PCT-RYZ C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Hie term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosacchari des, di saccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH₂, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen,

[0087] “Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C₁-C₉ heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In someAttorney Docket No. 01277-0089-00PCT-RYZ embodiments, monocyclic heteroaryl is a 5 -membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C₅-C₉ heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, tire heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom, A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0088] The term "‘moiety ” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0089] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease.

[0090] In certain embodiments, “treating” includes the concepts of “alleviating,” which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. In certain embodiments, the term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0091] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that in a statistical sample, reduces the occurrences of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0092] The term "therapeutically effective amount" as used herein refers to an amount effective at the0Attorney Docket No. 01277-0089-00PCT-RYZ dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0093] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g, -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CFI2CF3, -( T CH 3, -CFHCHF2, etc.).

[0094] As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to tlie core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

[0095] For the purpose of the disclosure, one event of “substitution” of an amino acid or an amino sequence is not considered two separate events of one deletion plus one addition. Thus, for the avoidance of doubt, as an example, a sequence change of “up to two deletion, substitution and / or addition” includes one deletion and one substitution, one deletion and one addition (at a different position), one substitution and one addition, one deletion only, one substitution only, one addition only, two deletions, two substitutions, two additions, etc. The deletion, addition, or substitution position may be at one or both ends of the peptide, or in the middle of the peptide.

[0096] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). For example, “optionally substituted” or “substituted” can mean that the referenced group is optionally substituted with one or more substituents individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some otherAttorney Docket No. 01277-0089-00PCT-RYZ embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), - N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, - S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Cj-Qalkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, C;-C4alkoxy, Ci-C4fluoroalkoxy, -SC]-C4alkyl, -S(=O)Ci-C4alkyl, and - S(:::O)2Cj-C4alkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, -CN, oxo, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci- C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alky4)2, -S(=O)(=NC)-C3alkyl)(C1-C3a]kyl), -NFL, -NHCi-Csalkyl, -N(Ci -C3alkyl)2, -N=S(=O)(C C3alky4)2, -C(=O)C;-C3alkyl, -C(=O)OH, - C(:::O)OCi-C3alkyl, -C(=O)NH2, -C(===O)NHC1-C3alkyl, -C(-O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, Ci-Csalkyl, Ci-Cgalkoxy, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, Ci-Cghydroxyalkyl, Ci-Cgaminoalkyl, Ci-Cgheteroalkyl, aryl, heteroary l, heterocycloalkyl and cycloalkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, -CN, oxo, - OH, -SF5, -SH, -S(===O)C1-C3alkyl, -S(===O)2Ci-C3alkyl, -S(==O)2NH2, -S(==O)2NHCi-C3alkyl, -S(==O)2N(Ci-C3alky 1)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), -NH2, -NHCi-C3alkyi, -N(Ci-C3alkyl)2, -N=S(=O)(C;- C3alkyl)2, -C(=O)Ci-C3alkyi, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(C,-C3alkyl)2> -P^OXCi- alkyl, C)-C3alkyl, C,-C3alkoxy, Ci-C3haloalkyl, -C^haloalkoxy, Ci-Cshydroxyalkyl, Ci-C3aminoalkyl, Ci-Csheteroalkyl, 5-6 membered heterocycloalkyl and C3-Cficycloalkyl. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents selected from halogen, oxo, -OH, -NH2, -NHCj-Csalkyl, -N(Ci-C3alkyl)2, -C(=O)OH, -C(=O)NH2, Ci-C3alkyl, ( -C alkoxw C, -C3haloalkyl, -Cjhaloalkoxy, Ci-Cshydroxyalkyl, Ci-C3aminoalkyl, Cj -C^heteroalkyl, and Cs-Cgcycloalkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), - CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (:::O). When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. In some embodiments, an “optionally' substituted” group is unsubstituted. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents. In some embodiments, an “optionally substituted” group is independently' substitued with 1-3 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1-2 substituents.

[0097] The term “unsubstituted” means that the specified group bears no substituents,

[0098] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0099] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.Attorney Docket No. 01277-0089-00PCT-RYZ

[0100] The term “peptide” as used herein refers to a compound that includes two or more amino acids. A peptide described herein can comprise one or more unnatural amino acids. The term “peptide” also encompasses peptide mimetics. In the present disclosure, the term “amino acid” is used in its broadest meaning and it embraces not only natural amino acids but also derivatives thereof and artificial amino acids. For example, the term “amino acid” encompasses unnatural amino acids.

[0101] The term “peptoid” as used herein refers to an N -substituted glycine. A peptoid can be optionally substituted, A peptoid can optionally comprise additional substitutions at the alpha-carbon.

[0102] As used herein, the term “unnatural amino acid” refers to an amino acid other than the 20 canonical amino acids. The 20 canonical amino acids refer to alanine (ala or A), arginine (arg or R), asparagine (asn or N), aspartic acid (asp or D), cysteine (cys or C), glutamine (gin or Q), glutamic acid (glu or E), glycine (gly or G), histidine (his or H), isoleucine (ile or I), leucine (leu or L), lysine (lys or K), methionine (met or M), phenylalanine (phe or F), proline (pro or P), serine (ser or S), threonine (thr or T), tryptophan (trp or W), tyrosine (tyr or Y), and valine (val or V).

[0103] The term “protein” as used herein refers to a polypeptide (i.e., a string of at least 3 amino acids linked to one another by peptide bonds). Proteins can include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or can be otherwise processed or modified. A protein can be a complete polypeptide as produced by and / or active in a cell (with or without a signal sequence). In some embodiments, a protein is or comprises a characteristic portion such as a polypeptide as produced by and / or active in a cell. A protein can include more than one polypeptide chain. For example, polypeptide chains can be linked by one or more disulfide bonds or associated by other means.

[0104] The term “peptide mimetic” or “mimetic” refers to biologically active compounds that mimic the biological activity of a peptide or a protein but are no longer entirely peptidic in chemical nature, e.g.„ they can contain non-peptide bonds (that are, bonds other than amide bonds between amino acids). As used herein, the term peptide mimetic is used in a broader sense to include molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Whether completely or partially non-peptide, peptide mimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resemble the three-dimensional arrangement of active groups in the subject amino acid sequence or subject molecule on which the peptide mimetic is based. As a result of this similar active-site geometry, the peptide mimetic can have effects on biological systems that are similar to the biological activity of the subject entity.

[0105] In some embodiments, the peptide mimetics are substantially similar in both three-dimensional shape and biological activity to the subject amino acid sequence or subject molecule on which the peptide mimetic is based. An example is described in the paper “Tritiated D-alal -Peptide T Binding”, Smith C. S. et al., Drug Development Res., 15, pp. 371-379 (1988). A second method is altering cyclic structure for stability', such as N to C interchain imides and lactams (Ede et al. in Smith and Rivier (Eds.) “Peptides: Chemistry’ and Biology”, Escom, Leiden (1991), pp. 268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third method is to substitute peptide bonds in the subject entity by pseudopeptide bonds that confer3Attorney Docket No. 01277-0089-00PCT-RYZ resistance to proteolysis.

[0106] The term “organic atoms” refers to atoms which would be found in organic compounds, such as carbon, hydrogen, nitrogen, oxygen, surfur, phosphorus, fluorine, chlorine, bromine, or iodine

[0107] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0108] As used herein, Ci-Cx(or Ci.x) includes C-i-C2, C1-C3... Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C]-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2 alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0109] The term “cyclized” or “cyclization” as used herein means that two ammo acids apart from each other by at least one amino acid bind directly or bind indirectly to each other in one peptide to form a cyclic structure in the molecule. In some cases, the two amino acids bind via a linker or the like.

[0110] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0111] Percent sequence identity can be calculated using computer programs or direct sequence comparison. Preferred computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package, FAS IA, BLASTP, and TBLASTN (see, e.g., D. W. Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory' Press, Cold Spring Harbor, N. Y.), The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine percent identity.Exemplary parameters for amino acid sequence comparison include the following: 1) algorithm from Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) BLOSSUM62 comparison matrix from Hentikoff and Hentikoff (Proc. Nat, Acad. Sei. USA., 89: 10915-109 IS) (1992)) 3) gap penalty=12; and 4) gap length penal ty =4. A program useful with these parameters can be publicly available as the “gap” program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are the defaultAttorney Docket No. 01277-0089-00PCT-RYZ parameters for polypeptide comparisons (with no penalty for end gaps). Alternatively, polypeptide sequence identity can be calculated using the following equation: % identity' - (the number of identical residues) / (alignment length in amino acid residues)* 100, For this calculation, alignment length includes internal gaps but does not include terminal gaps.

[0112] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment.Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a conjugate of this disclosure can comprise any peptide ligand described herein (e.g., a peptide of Formula (I) or (II), or Table 1, 2, 3, 4, or 9 A), any metal chelator described herein (e.g., a metal chelator selected from FIGs 1 A, 2A, 3A, 4A, IB, 2B, 3B, 4B and 5-19), optionally a linker described herein (e.g., a linker of Formula (II- 1), (II- la), or (II- lb)), and optionally a radionuclide described herein (e.g., a radionuclide of Table 10).

[0113] Unless special definitions are given, the terminology used in relation to analytical chemistry, synthetic organic chemistry’, and medical chemistry' and pharmaceutical chemistry' described in the present specification, as well as their procedures and techniques, are well known and commonly used in the field of the present art. Standard techniques may be used for chemical synthesis and chemical analysis. Those defined from among such techniques and procedures can be found in, for example, “K. Jensen, P. T. Shelton, S I.. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013” and the like, and these are incorporated into the present specification by reference for all purposes. All patents, applications, published applications, and other publications, and other data referred to throughout the entire disclosure, when permitted, are incorporated into the present specification by reference.II. Conjugates

[0114] Provided herein are conjugates that have avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising the conjugates. The conjugates and compositions can be useful for treating cancer. The conjugates and compositions can also be useful in imaging and disease diagnosis.

[0011] In one aspect, described herein is a conjugate that comprises a peptide that has avidity for Glypican 3 (GPC3) and a metal chelator that is configured to bind with a radionuclide. In some embodiments, the GPC3 is a human GPC3. The peptide can be cyclic or acyclic, and it can be monocyclic, bicyclic or polycyclic. In one aspect, described herein is a conjugate that comprises a cyclic peptide and a metal chelatorthat is configured to bind with a radionuclide. In some embodiments, the peptide (such as cyclic peptide) is configured to bind to a target. A conjugate described herein can further comprise a linker that covalently connects the peptide to the metal chelator. In some embodiments, the conjugate comprises a radionuclide such as223Ac bound to the metal chelator.

[0116] In another aspect, described herein is a conjugate that composes a peptide that has avidity' for Glypican 3 (GPC3) and a covalently bound radionuclide. In some embodiments, the GPC3 is a human GPC3. The peptide can be cyclic or acyclic, and it can be monocyclic, bicyclic or polycyclic. In oneAttorney Docket No. 01277-0089-00PCT-RYZ aspect, described herein is a conjugate that comprises a cyclic peptide and a metal chelator that is configured to bind with a radionuclide. In some embodiments, the peptide (such as cyclic peptide) is configured to bind to a target, A conjugate described herein can further comprise a linker that links the covalent radionuclide to the peptide. In some embodiments, the conjugate comprises a covalent radionuclide such as1311 bound.

[0117] Peptides, linkers, and radionuclides suitable for use in the conjugates provided herein are as described herein.

[0118] In some embodiments, the conjugate comprises a metal chelator configured to bind with a radionuclide, in some embodiments, the conjugate comprises a radionuclide bound to the metal chelator. In some embodiments, the conjugate comprises a covalently bound radionuclide.

[0119] In some embodiments, the conjugate comprises a metal chelator configured to bind with a radionuclide, wherein the metal chelator is bound to the peptide. In some embodiments, the metal chelator is covalently linked to the peptide. In some embodiments, the conjugate further comprises a linker that connects the peptide with the metal chelator. In some embodiments, the linker covalently connects the peptide with the metal chelator. In some embodiments, the linker covalently attaches the metal chelator to the N-terminus of the peptide. In some embodiments, the linker covalently ataches the metal chelator to the C-terminus of the peptide. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to amino acid XI. In some embodiments, the linker is attached to amino acid X2. In some embodiments, the linker is atached to amino acid X3. In some embodiments, the linker is attached to amino acid X4. In some embodiments, the linker is attached to amino acid X5. In some embodiments, the linker is attached to amino acid X6. In some embodiments, the linker is attached to amino acid X7. In some embodiments, the linker is attached to amino acid X8. In some embodiments, the linker is attached to amino acid X9. In some embodiments, the linker is attached to amino acid X10. In some embodiments, the linker is atached to amino acid XI 1. In some embodiments, the linker is attached to amino acid XI 2. In some embodiments, the linker is attached to amino acid XI, X2, X3, X4, X8, or X12. in some embodiments, the linker is attached to a lysine of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises a lysine residue, an alanine residue, a glycine residue, a D-phenylalanine residue, a histidine residue, a dAtb residue, or a D-glutamate residue. In some embodiments, the linker comprises 2 amino acids selected from the group consisting of lysine, alanine, glycine, D-phenylalanine, histidine, dAtb, and D-glutamate. In some embodiments, the linker is a Ci-6 heteroalkylene. In some embodiments, the peptide is directly attached to the metal chelator.

[0120] In some embodiments, the metal chelator is covalently attached to the side chain of tire first amino acid of the peptide (X;, Ai), the side chain of the second amino acid of the peptide (X2, A2), the side chain of the third amino acid of the peptide (X3, A3), the side chain of the fourth amino acid of the peptide (X4, A4), the side chain of the eighth amino acid of the peptide (Xs, As), or to the C-terminus of the C-terminal amino acid of the peptide (X12, Q, when Q is -NH2); or wherein the peptide comprises a thirteenth amino acid and the metal chelator is covalently attached to the side chain of the thirteenthAttorney Docket No. 01277-0089-00PCT-RYZ amino acid (XB, Q, when Q is D-Lys).

[0121] In some embodiments, the conjugate comprises a covalently bound radionuclide. In some embodiments, the conjugate further comprises a linker that connects the peptide with the covalently bound radionuclide. In some embodiments, the linker covalently connects the peptide with the covalently- bound radionuclide. In some embodiments, the linker covalently attaches the covalently bound radionuclide to the N-terminus of the peptide. In some embodiments, the linker covalently7attaches the covalently bound radionuclide to the C -terminus of the peptide. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid residue of the peptide. In some embodiments, the linker is attached to amino acid XI. In some embodiments, the linker is attached to amino acid X2. In some embodiments, the linker is attached to amino acid X3. In some embodiments, the linker is attached to amino acid X4. In some embodiments, the linker is attached to amino acid X5. In some embodiments, the linker is attached to amino acid X6. In some embodiments, the linker is attached to amino acid X7. In some embodiments, the linker is attached to amino acid X8. In some embodiments, the linker is attached to amino acid X9. In some embodiments, the linker is attached to amino acid XIO. In some embodiments, the linker is attached to ammo acid XI 1, In some embodiments, the linker is attached to amino acid X12, In some embodiments, the covalently bound radionuclide is directly covalently bound to an amino acid comprising an aromatic ring. In some embodiments, the covalent radionuclide is directly covalently bound to X5, X8, X9, X4, or XI 1.

[0122] In some embodiments, described herein is a conjugate comprising: (a) a targeting moiety that comprises a monocyclic peptide that has avidity for Glypican 3 (GPC3), or a pharmaceutically acceptable salt thereof, and (b) (i) a metal chelator configured to bind with a radionuclide, wherein the metal chelator is bound to the peptide, or (ii) a covalently bound radionuclide, in some embodiments, described herein is a conjugate comprising: a monocyclic peptide that is configured to bind with GPC3 and a metal chelator configured to bind with a radionuclide. In some embodiments, described herein is a conjugate comprising: a monocyclic peptide that is configured to bind with GPC3 and a covalently bound radionuclide, in some embodiments, the monocyclic peptide is cyclized by a non -disulfide bond. In some embodiments, the monocyclic peptide does not comprise a disulfide bond. In some embodiments, the monocyclic peptide comprises 5 to 20 amino acid residues. In some embodiments, the monocyclic peptide comprises 7 to 14 amino acid residues. A conjugate described herein can further comprises a linker that covalently7connects the cyclic peptide to the metal chelator or covalent radionuclide. In some embodiments, the conjugate comprises a radionuclide such as225Ac bound to the metal chelator, or121I bound to the cyclic peptide.

[0123] In some embodiments, a herein-described conjugate is in a salt form (e.g., pharmaceutically acceptable salt form). In some embodiments, a herein-described conjugate is in a free-base form.

[0124] In some embodiments, a conjugate of the present disclosure is a conjugate from Table 5, 6, 7, 8, or 9B, In some embodiments, a conjugate of the present disclosure comprises a peptide of Table 1, 2, 3, 4, or 9A, a chelator from FIGs. 1-19, and a radionuclide of Table 10.7Attorney Docket No. 01277-0089-00PCT-RYZ Conjugate Having GPC3 Avidity

[0125] Glypican-3 (GPC3) is a protein that in humans is encoded by the GPC3 gene. GPC3 may be upregulated in multiple cancers, often correlating with disease progression, metastasis and poor prognosis e.g., in solid tumors such as hepatocellular, lung, gastric, and ovarian.

[0126] GPC3 belongs to the sulfate heparin proteoglycan family, and is anchored on the cell membrane surface by phosphatidylinositol (GPI) anchor.

[0127] GPC3 can play an important role in the cell proliferation of embryo layer tissue. Deletion of GPC3 gene can cause excessive growth syndrome, namely Simpson-Golabi-Behmel syndrome (SGBS). GPC3 can be expressed throughout the entire fetal stage, and after birth to adult stage, except for placental, breast, mesodermal, ovarian, lung and kidney tissue with weak expression, other normal tissues have no obvious expression.

[0128] In some embodiments, the conjugate of the present disclosure binds to GPC3. In some embodiments, the conjugate has GPC3 antagonistic activity. In some embodiments, the conjugate binds to human GPC3 (hGPC3) and has hGPC3 antagonistic activity, such as inhibiting tire ability of GPC3 to promote or stabilize Wnt / ' Frizzled interaction and / or downstream signaling.

[0129] As used herein, the term “GPC3” refers to any form of GPC3 and a variant thereof for retaining at least a part of the activity of GPC3. The GPC3 includes all the native sequences of GPC3 in mammals such as, for example, humans, dogs, cats, horses, and cows, unless otherwise specifically described as human GPC3 (11GPC3). One exemplification of GPC3 is hGPC3 (Gene ID:27I9), which is human GPC3 and is a protein having an amino acid sequence (Isoform 1, P51654-1):MAGTVRTACLVVAMLLSLDFPGQAQPPPPPPDATCHQVRSFFQRLQPGLKWVPETPVPGSDLQV CLPKGPTCCSRKMEEKYQLTARLNMEQLLQSASMELKFLIIQNAAVFQEAFEIVVRHAKNYTNA MFKNNYPSLTPQAFEFVGEFFTDVSLYILGSDINVDDMVNELFDSLFPVIYTQLMNPGLPDSALDI NECLRGARRDLKVFGNFPKLIMTQVSKSLQVTRIFLQALNLGIEVINTTDFILKFSKDCGRMLTRM WYCSYCQGLMMVKPCGGYCNVVMQGCMAGVVEIDKYWREYILSLEELVNGMYRIYDMENVL LGLFSTIHDSIQYVQKNAGKLTTT1GKLCAHSQQRQYRSAYYPEDLFIDKKVLKVAHVEHEETLS SRRRELIQKLKSFISFYSALPGYICSHSPVAENDTLCWNGQELVERYSQKAARNGMKNQFNLHEL KMKGPEP SQIIDKLKHINQLLRTMSMPKGRVLDKNLDEEGFESGDCGDDEDECIGGSGDGMI KVKNQLRFLAELAYDLDVDDAPGNSQQATPKDNE1STFHNLGNVHSPLKLLTSMA1SVVCFFFL VH (SEQ ID NO: 500).

[0130] As used herein, the expression “has avidity for GPC3"’ or “binds to GPC3” indicates the activity of binding to GPC3. Binding site of the peptide of the present disclosure on the GPC3 is not limited, the peptide can bind to anywhere on the GPC3 protein. Binding to GPC3 may be measured by any method for measuring known intermolecular binding. In a non-limiting manner, for example, this may be determined by competitive binding assays such as surface plasmon resonance (SPR) assays, scatter analysis and / or radioimmunoassays (RIA), enzyme immunoassays (ETA), and sandwich and competitive assays, and in any suitable manner which is known, including different variants of the examples given that are known in the technical field.Attorney Docket No. 01277-0089-00PCT-RYZ

[0131] In one aspect, the binding affinity of the conjugate of the present disclosure is at most 100 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some implementations, the Kd of the peptides of the conjugates disclosed herein is 100 nM or less, 50 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, 0.03 nM or less, 0.02 nM or less, 0.01 nM or less.

[0132] In some embodiments, a conjugate described herein has a binding affinity to a human GPC3 of at most I, 5, 10, 50, 100, 200, 500, 1000, 5000 or 10,000 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human GPC3 of at most J OOnM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human GPC3 of at most 1 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human GPC3 of at most 2 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human GPC3 of at most 5 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, a conjugate described herein has a binding affinity to a human GPC3 of at most 10 nM as determined by Kd in surface plasmon resonance (SPR) analy sis.

[0133] In one aspect, the binding affinity of the peptide or conjugate of the present disclosure is at most 100 nM as determined by Kd in surface plasmon resonance (SPR) analysis. In some embodiments, the Kd of the peptide or conjugate of the present disclosure is 100 nM or less, 50 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, I nM or less, 0.9 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, 0.03 nM or less, 0.02 nM or less, 0.01 nM or less.GPC3 Peptide Binding Ligand

[0134] In one aspect, the disclosure relates to a conjugate comprising a peptide (e.g., a binding peptide) that has avidity for Glypican-3 (GPC3). The GPC3 can be a mammalian GPC3, The GPC3 can be a human GPC3. The GPC3 can be a wild-type or mutated GPC3. In some embodiments, the conjugate of the disclosure comprises two or more peptides, which can be the same or different. The peptide can be linear or cyclic. In some embodiments, the peptide is monocyclic. The peptide can comprise any suitable number of amino acid residues. In some embodiments, the peptide comprises from 5 to 50, 6 to 40, 7 to 30, 8 to 25, 12 to 25, or 9 to 20 amino acid residues. In some embodiments, the peptide comprises from 5 to 14 amino acid residues. In some embodiments, tire peptide comprises from 7 to 12 amino acid residues. In some embodiments, the peptide comprises from 8 to 12 amino acid residues. In some embodiments, the peptide comprises from 8 to 10 amino acid residues. In some embodiments, the peptide comprises from 7 to 13 amino acid residues. In some embodiments, the peptide comprises from 12 to 15Attorney Docket No. 01277-0089-00PCT-RYZ amino acid residues. In some embodiments, tire peptide comprises from 13 to 14 amino acid residues. In some embodiments, the peptide comprises 6 amino acid residues. In some embodiments, the peptide comprises 7 amino acid residues. In some embodiments, the peptide comprises 8 ammo acid residues. In some embodiments, the peptide comprises 9 amino acid residues. In some embodiments, the peptide comprises 10 amino acid residues. In some embodiments, the peptide comprises 11 amino acid residues. In some embodiments, the peptide comprises 12 amino acid residues. In some embodiments, the peptide comprises 13 ammo acid residues. In some embodiments, the peptide comprises 14 amino acid residues. In some embodiments, the peptide comprises 15 amino acid residues. In some embodiments, the peptide comprises 16 amino acid residues. In some embodiments, the peptide consists of 6 amino acid residues. In some embodiments, the peptide consists of 7 amino acid residues. In some embodiments, the peptide consists of 8 amino acid residues. In some embodiments, the peptide consists of 9 amino acid residues. In some embodiments, the peptide consists of 10 amino acid residues. In some embodiments, the peptide consists of 11 amino acid residues. In some embodiments, the peptide consists of 12 amino acid residues. In some embodiments, the peptide consists of 13 amino acid residues. In some embodiments, the peptide consists of 14 amino acid residues. In some embodiments, the peptide consists of 15 amino acid residues. In some embodiments, the peptide consists of 16 amino acid residues. In some embodiments, the conjugate comprises a monocyclic peptide of 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. A peptide described herein can be a binding peptide that binds to GPC3. In some embodiments, the binding peptide consists of 6 to 20 ammo acid residues. In some embodiments, the binding peptide consists of 7 to 12 amino acid residues. In some embodiments, the binding peptide consists of 10 to 12 amino acid residues. In some embodiments, the binding peptide consists of 8 to 12 amino acid residues. In some embodiments, the binding peptide is monocyclic. In some embodiments, the peptide of the present technology is an isolated peptide. In some embodiments, the peptide of the present technology is a purified peptide.

[0135] In one aspect, the peptide is of Formula I:Formula I,wherein:R is -CH2-CO-; and(i) X; is MeLys, MeLysAc, MeAla, MeGlu, MeGln, or CrpG, wherein the N-terminal nitrogen of Xi is attached to the C(O) of R; andX2 is Melle, MeGln, MeLys, MeHseMe, MeLysCOpipzaa, or MeGlu; andAttorney Docket No. 01277-0089-00PCT-RYZ X3is Asp, MeAsp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andX4is MeGln, MeLys, MeAspapCOpipzaa, MeGlu, or CrpG; andX, is F4COO, MeF4C00, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andX6is TMe, altMe, He, or Leu; andX7 is TMe, He, Vai, Leu, Gcpe, or Eva; andXgis Tyr, Cha, F3OII, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py 6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; andX9is MeNal27N, MeF3Me4C, MeF34dOMe, or MeW7N; andX10 is Gly, MeGly, D-Ala, D-Ser, or D-Pro; andXu is 3Py6Ph, 3Py6PyrazolI, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4pipl Ac, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; andX12 is MeCys or Cys, wherein sulfur of the X12 side chain is covalently attached to R, ~ CK, NH2O y2N N H2and carboxylic acid of X] 2 is replaced with -C(0)NH2 orH;and wherein Xi is MeGlu or CrpG; or X2 is MeLys; or X3is MeAsp, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or X4is MeGlu, or CrpG; or X5is MeF4C00, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; or Xf, is alTMe or Leu; or X? is TMe, Vai, Leu, Gcpe, or Eva; or X8is Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or X9is MeF3Me4C, MeF34dOMe, or MeW7N; or X10 is MeGly, D-Ala, D-Ser, or D-Pro; orXn is 3Py6Pyrazoll, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; orX^is Cys; or(ii) X] to Xj2 have a sequence from Table 1, 2, 3, 4, 9A, or 20A (and, in some further aspects, from Table 1, 2, 3, 4, or 9A).

[0136] In one aspect, the peptide is of Formula II:Attorney Docket No. 01277-0089-00PCT-RYZFormula IIwherein:R* is -CH2-S-CH2-CO-;each Z is independently selected from H and Me; ando. NH2NNH2Qis -NIL or H; and(i) Ai is the side chain of Lys, LysAc, Ala, Glu, Gin, or CrpG; andA2is the side chain of lie, Gin, Lys, HseMe, LysCOpipzaa, or Glu; and As is the side chain of Asp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andA4 is the side chain of Gin, Lys, AspapCOpipzaa, Glu, or CrpG; andAs is the side chain of F4COO, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andAs is the side chain of TMe, altMe, He, or Leu; andA? is the side chain of Tme, He, Vai, Leu, Gcpe, or Eva; andA« is the side chain of Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; and A9 is the side chain of Nal27N, F3Me4C, F34dOMe, or W7N; andAjo is the side chain of Gly, D-Ala, D-Ser, or D-Pro; andAn is the side chain of 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4pip lAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C;and wherein Ai is the side chain of Glu or CrpG; or A2is the side chain of Lys; or As is the side chain of Asp, Ser, Thr, Ala, or Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or A4 is the side chain of Glu or CrpG; or A 5 is the side chain of F4COO, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; or AgAttorney Docket No. 01277-0089-00PCT-RYZ is the side chain of alTMe or Leu; or A? is the side chain of Tme, Vai, Leu, Gcpe, or Eva; or As is the side chain of Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or Ao is the side chain of F3Me4C, MeF34dOMe, or MeW7N; or Aio is the side chain of Gly, D-Ala, D-Ser, or D-Pro; or Ai i is the side chain of 3Py6Pyrazol 1, 3Py6O4pip IMs, 3Py6O4pip 1 Ac, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; or (ii) Ai to An correspond to the side chains of X;to Xu of a sequence from Table 1, 2, 3, 4, 9A, or 20A (and, in some further aspects, from Table 1, 2, 3, 4, or 9A).

[0137] In one aspect, Xi to X]2of the peptide of Formula (I) have a sequence from Table 1, 2, 3, 4, 9A, or 20A. In one aspect, X;to X] 2of the peptide of Formula (I) have a sequence from Table 1, 2, 3, 4, or 9A. In a further aspect, Xi to Xi2of the peptide of Formula (I) have the sequence of SEQ ID NO: 226, 520, or 521.

[0138] In one aspect, the peptide does not have a sequence from Table A, In one aspect, the peptide is not any of SEQ ID NOS: 1-72.

[0139] A list of natural amino acids is found in Table AA. It is understood that “Me"’ as a prefix for any of the amino acids of Table AA represents the V-methylated version of that ammo acid (e.g.: MeAla or MeA is JV-methylalanine, etc.). It is also understood that“L-“ or “L” as prefix for any of the amino acids of Table AA represents the D-stereoisomer or L-stereoisomer of that amino acid (e.g.: D- Ala or D-A is D-alanine, L-Ala or L-A is L-alanine, etc.).Table AA: List of natural amino acidsA Ala AlanineR Arg ArginineN Asn AsparagineD Asp Aspartic acid / AspartateC Cys CysteineQ Gin GlutamineE Glu glutamic acid / glutamateG Gly GlycineH His HistidineI lie IsoleucineL Leu LeucineK Lys LysineM Met MethionineF Phe PhenylalanineP Pro ProlineS Ser SerineT Thr ThreonineAttorney Docket No. 01277-0089-00PCT-RYZ w Trp TryptophanY Tyr TyrosineV Vai Valine

[0140] Unless otherwise stated in the present specification, the following abbreviations for non-natural amino acids (abbreviations indicated in bolded text in the table below) are used according to the following meanings:Attorney Docket No. 01277-0089-00PCT-RYZ1 0 0 0 J P(R) Y OH \ JMSIXNH2o tsjy OHu U> V NH H2NH2 2NNH2(2S,3^)-2-amino-3- (S)-2-amino-3-(4- (5>2 -aminobutanoic acid (9-methyl-Z -allothreoninemethylpentanoic acid aminophenyl)propanoic acid Abu alTMeall Aph0 00 0 O n H ii NH2NHo HO '-' '-' "■' OH H2N^X^2| X 'OH< / NH24_(5)-2-amino-3- 1 -aminocyclopentane- 1 - ( (carboxymethyl)am ino)butano cyclohexylpropanoic acid (S)-2-amino-3-(4'-chloro-[l, 1'- carboxylic acidic acidCha bipheny 1] -4-y l)propanoic acid CleCrpG Bph4CO p0 HO." jd OH Its;H2N NH21NH2NH2NH2(5)-2-amino-3- (S)-2-amino-3-(3- (S)-2-amino-3 -ethylpentanoic(5)-2,3-diaminopropanoic acid(dimethylamino)propanoic acid hydroxyphenyl)propanoic acid acidDapdiMeDap F3OH EvaAttorney Docket No. 01277-0089-00PCT-RYZ00, O.o 02'f / x A NH '2N N O NH rN T N N N OijAAySH HO^VM1-N^HOHM0^A[i i T0HOH06 HO. Y 0 A NH2. NH22HO ~2(< S)-2-amino-3-(4-(2-(4- (5’)-2-amino-3-(4-((4- 0(carboxymethyl)piperazin- 1 - (5)-2-amino-3-(4- (5)-2-amino-3-(4- (carboxymethyl)pi perazine - 1 - yl)-2- (carboxymethyl)phenyl)propan (carboxymethoxy)phenyl)propa carboxami do)methyl)pheny 1 )proxoethoxy)phenyl)propanoic oic acid noic acid opanoic acidacid F4aa F4aao F4ainCOpipzaaF4aaopipzaa0 O0OH 1 NH2NH2NH2NH20 0 FO(S)-2-amino-3-(4- (S)-2-amino-3-(4- (5)-2-amino-3-(4- (5)-4-(2-amino-2- (dimethylcarbamoyl)phenyl)pr (methylcarbamoyl)phenyl)prop fluorophenyl)propanoic acid carboxyethyl)benzoic acidanoic acid opanoic acid F4FF4COOF4CONMe2 F4CONHMeAttorney Docket No. 01277-0089-00PCT-RYZo0 0 o YYK °Ho irv^w"e-AYNH2 A A J NH,oHNH2 / — N 7NH22— N ^7H, N N2H NHO" % H(5)-2-amino-3-(4-(l-(3- (S)-2-amino-3 -(4-( 1 -methyl - (5)-2-amino-3-(4- (< S)-2-amino-3-(4- aminopropyi)- 1 / / -pyrazol-4- 127-pyrazol-4- sulfophenyl)propanoic acid ureidophenyl)propanoic acidyl)pheny])propanoic acidyl)phenyl)propanoic acid F4SO3H F4UF41apPyzF41Me4Pyz q 00 0 n '3 OH[T' OH NH2^N^YYY NH2NH2YL Y NH2V" HN^J(25)-2-amino-3-|4-(5- (25)-2-amino-3-[4-(2-oxo- 1,2- (2;S,)-2-amino-3- [4-(pyridin-2- (2;S,)-2-amino-3-(4-(pyridin-4- hydroxypyridin-3 - dihydropyridin-4- yl)phenyl]propanoic acid yl)phenyl)propanoic acid yl)phenyl]propanoic acid yl)phenyl]propanoic acidF42Py F44Py F43Py5H F44Pdo0 0 0 / A 0 HO J\ 1 I H2K. JY ^0^ AY2b NH20HNH2NH NH2(5)-2,6-diamino-6-oxohexanoic (25)-2-amino-4- (5)-2-amino-3 -hydroxy-3 - (S)-2-amino-2- cyclopentylacetic acid acid methoxybutanoic acid methylbutanoic acid GcpeHgn HseMe HvaAttorney Docket No. 01277-0089-00PCT-RYZ0 o oOu0Q OH\ N HN^H0KXN. A HN^ VYY™ A 1 fs; OHc,xW HN^ d NH2(< S)-3-(l- (, S)-3-(4- (S)-3-(4-chloro-3- (2S)-2-amino-6- (carboxymethyl)piperidin-4- (carboxymethyl)piperazine- 1 - methylphenyl)-2- acetamidohexanoic acid yI)-2-(methylamino)propanoic carboxamido)-2- (methylamino)propanoic acid Kyle acid (methy Iamino)propanoic aci dMeF3Me4C MeA4paa MeDapCOpipzaa0 0 OL - A -°YYA°Hx°^y<0H / vyA ™ < ii T AkAhn\ AAAHN\ HN^(S)-3 -( 1 -methyl- lZ / -indazol-6- (S)'-3 -( 1 -methyl- lZf-indol-6- (25)-4-methoxy-2- (5)-3-(3,4-dimethoxyphenyl)-2- yl)-2-(methylamino)propanoic yl)-2-(methylamino)propanoic (methylamino)propanoic acid (methylamino)butanoic acidacid acid MeF34dOMe MellseMeMe(7Me)6inda Me(7Me)6indol HO. x-x„x-xH 0 6 kH u0A OH N-. x^x^... x^ JI\zN / A O7T i- N II T A0HCJLZA. / °fs>OHvA HN^ 0 HN^ (25)-6-{[4- -NA \)H (carboxymethyl)piperazine- 1 - (S)-3-(l / Z-indazol-6-yl)-2- (2S)-6-acetamido-2- methyl-Z-tryptophan carbonyl] amino } -2 - (methylamino)propanoic acid (methylamino)hexanoic acidMeiW (methylamino)hexanoic acid Me6inda MeKAcMeKCOpipzaaAttorney Docket No. 01277-0089-00PCT-RYZUNH2HH*?H2HH2NH H, T2H H fRJJN ✓x -, N <? A.Y I0 jx 1 n 1 lx 0 / Yx HO T'O o °HO^o f,N. HO"% [^ ) HOX'O i HN—1A^-(D-ghitamy3)-¥2-methyl-Z- ¥6-((77)-2-amino-4,4- Ar6-(Z-histidyl)-Ar2-methyl-Z,- A6-(D-phenylalanyl)- / V2- lysine dimethylpentanoyl)-jV2-methyl- lysine methyl-Z-lysineMeK(de) Z-Iysine MeK(H) MeK(df) MeK(datb)0 0 ^NH JTN\L 0HOx.O^IT^OH oHN\ HN^ Y / NH(S)-2-(methylamino)-3 -( 1 / 7- (S)-2-(methylamino)-3- (25,37?)-3-methoxy-2- (S) -morphol ine-3 -carboxylic pyrrolo [2,3 -b]pyridin-3 - (pyridin-3 -yl)propanoic acid (methylamino)butanoic acid acid yi)propanoic acidMe3Py MeTMe (S)Mor(2CO)MeW7N0 O O 0i^Y 'iPr OH / \fsdk OH[f0HHN^ V Y OH N / )■ NH? NH2HN\(N)-2-(methylamino)-3- (5)-3-(isoquinolin-7-yl)-2- (naphthalen-2-yl)propanoic (S)-2-amino-3-(4-(pyridin-2- (5)-2-amino-3-(4-(pyridin-3- (methylamino)propanoic acidacid yl)phenyl)propanoic acid yl)phenyl)propanoic acid MeNaI27NMeNal2 Phe(4-(2-Py)) Phe(4-(3-Py))Attorney Docket No. 01277-0089-00PCT-RYZO(S)-2-amino-3-(2- (S)-3 -(6-( 127-itnidazol- 1 - (5T)-2-amino-3-(4-(pyridin-4- (5)-5-(2-amino-2- pheny lpyrimidin-5 - y l)pyriditi-3 -yl)-2- yl)phenyl)propanoic acid carboxyethyl)picolinic acidyl)propanoic acid aniinopropanoic acid Phe(4-(4-Py)) 3py6COOPhe35N4Ph 3Py6Imidazl ON iT i (S) OHAA NH2(5)-2-amino-3-(6- (5)-2-amino-3-(6- (25)-3 - { 6-[( 1 -acetylpiperidin-4- (S)-2-amino-3-(6- methylpyridin-3-yl)propanoic aminopyridin-3 -y l)propanoic yl)oxy]pyridin-3-y1 }-2- ((carboxymethyl)amir!o)pyndinacid acid aminopropanoic acid -3-yl)propanoic acid3Py6Me 3py6NH2 3py6O4piplAc3py6NHaaAttorney Docket No. 01277-0089-00PCT-RYZ(25')-2-amino-3-{6-|(l- methanesulfonylpiperidin-4- (2;S,)-2-amino-3-[6-(oxan-4- (S)-2-amino-3-(6- yloxy)pyridm-3-yl]propanoic (5)-2-amino-3-(6-(oxazol-5- yl)oxy]pyridin-3-yI}propanoic phenylpy ridin-3 -yl)propanoic yl)pyridin-3-yl)propanoic acidacid acidacid 3py6O4thp 3Py6Oxaz53py6O4piplMs 3py6ph(< S)-2-amino-3 -(6-(piperazin- 1 - (, S)-2-amino-3 -(6-(piperidin- 1 - (S)-2-amino-3-(4-(pyridin-2- (5)-2-amino-3-(4-(pyridin-3- yl)pyridin-3 -yl)propanoic acid yl)pyridin- 3 -yl)propanoic acid yl)phenyl)propanoic acid yl)phenyl)propanoic acid 3Py6Pipza 3Py6(Pipl) 3Py(6-(2-Py)) 3Py(6-(3-Py))Attorney Docket No. 01277-0089-00PCT-RYZ0 O 0 0NYV^OHOHNH2NH2NH2NH2HN JA A(5)-3-(6-(lH-pyrazol-l - (< S)-3-(6-( lH-pyrazol-3- (5)-3 -(6-( 1 / / -pyrrol- 1 - (tS)-2-a3iiino-3-(4-(pyridin-4- yl)pyridin-3-yl)-2- yl)pyridin-3 -yl)-2- yl)pyridin-3 -yl)-2- yl)phenyl)propanoic acidaminopropanoic acid aminopropanoic acid aminopropanoic acid 3Py(6-(4-Py))3py6Pyrazoll 3Py6Pyrazo!3 3Py6PyrroIl 0 0A 0F0He |YJA> H 0 AJ NH, f'' HO. X > NH2 / X27NJ- NHoH N N- X N2ONN N^A NH2(25')-2-amino-3-{6-[l-(3- (2S)-2-am i no-3 - { 5 '-hydroxy- (5)-2-ainino-3-(pyridin-4- aminopropyl)- 17 / -pyrazol-4- (25)-2-ainino-3-{[2,3'- [2, 3 ' -bi pyridin] -5 -yl } propanoic yl)propanoic acid yl]pyridin-3-yl}propanoic acid bipyridin] -5 -yl} propanoic acidacid 4py 3py61ap4pyz 3py63Py3py63Py5H0OHH OH 0 0 \\ / Y YC OH = 0 / \X II \ A / stA,HO V NH2OH \ xxA.NH20 ff?A(0HA NH2(5)-5-(2-amino-2- NH2(25',3J?)-2-amino-3- (.8>2-amino-3-(lH-pyrrolo[3,2- carboxy ethyl)- lH-pyrrole-2- O-methyl-Z-threoninehydroxypentanoic acid c]pyri din-3 -yl)propanoi c acid carboxylic acid TMeS3REt W5N(PyrrCOO)AAttorney Docket No. 01277-0089-00PCT-RYZ0 on H AfOHAYAT °Ho ANyNA A N H2H2N^x\ NH20(S)-2-amino-3 -(4-(2 -aminoethoxy )phenyl)propanoic acid (S)-2-amino-3-(4-(2-(4-(carboxymethyl)piperazine-l- Yae carboxamido)ethoxy)phenyl)propanoic acid YaeCOpipzaa0 ON0HNH2H2\ iV V-N(5)-2-amino-3-(6-(4-methyl-l / / -imidazol-l-yl)pyridin-3- (5)-2-amino-3-(6-(4-methyI-lZf-pyrazoI-l-yl)pyridin-3- yl)propanoic acid yl)propanoic acid3Py6 (4MeImi daz 1 ) 3py6(4MePyrazoll)0O1NH2HO^Y^NH20 AN(S)-2-amino-3-(4-(hydroxy(methyl)carbamoyl)phenyl)propanoic(, S)-2-amino-3 -( 6 -(3 -methyl- 1 J7-pyrazol- 1 -yl)pyridin-3 - acidyl)propanoic acid F4(CONMeOH)3py6(3MePyrazoll)Attorney Docket No. 01277-0089-00PCT-RYZTable A. Example peptide sequences with avidity to GPC3 (“Term” refers to the functional group at the C-terminus)Peptide Sequence?rom residue position 1 to residue position 15, if present)SEQ I 1 11 2 3 4 5 6 7 8 9 10 11 12 Term ID No. 3 4 5 1 MeK Mel D MeQ F4COO I I Y MeNal27N G 3Py6Ph MeC NH22 MeKAc Me! D MeQ F4COO I I F4COO MeNal2 G 3Py6Ph MeC NH23 MeKAc Mel D MeQ F4COO I I F4COO MeNal2 G F4J Me4Pyz MeC NH24 MeKAc Mel Q MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NFI25 MeK Mel D MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH26 MeK Mel Q MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH2 / MeKAc Mel D MeQ F4COO I I Y MeNal27N G 3Py6Ph MeC NH28 MeQ MeQ D MeQ F4COO! I F4COO MeNal2 G F4J Me4Pyz MeC NH29 MeA MeQ D MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH210 MeQ MeL D MeQ F4COO I I F4COO MeNal2 G F4J Me4Pyz MeC NH211 MeQ MeHseMe D MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NFI212 MeQ HseMe D MeQ F4COO I I F4COO MeNal2 G F4J Me4Pyz MeC NH213 MeQ MeQ Hgn MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH214 MeQ MeQ KAc MeQ F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH215 MeQ MeQ D MeA4paa F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH216 MeQ MeQ D MeD F4COO I I F4COO MeNal2 G F41Me4Pyz MeC NH217 MeQ MeQ D MeQ F4aao! I F4COO MeNal2 G F4J Me4Pyz MeC NH218 MeQ MeQ D MeQ F4COO TMe I F4COO MeNal2 G F41Me4Pyz MeC NFI219 MeQ MeQ D MeQ F4COO I I F4aa MeNal2 G F4J Me4Pyz MeC NH220 MeQ MeQ D MeQ F4COO I I F4aao MeNal2 G F4J Me4Pyz MeC NH221 MeK MeHseMe D MeQ F4COO I I F4aa MeNal2 G 3Py6Ph MeC NH222 MeK MeHseMe D MeQ F4COO I I F4aa MeNal2 G F41Me4Pyz MeC NH223 MeK MeHseMe D MeA4paa F4COO I I F4aa MeNal2 G F41Me4Pyz MeC NH2Attorney Docket No. 01277-0089-00PCT-RYZPeptide Sequence?rom residue position 1 to residue position 15, if present)SEQ 1 i 11 2 3 4 5 6 7 8 9 10 11 12 Term ID No. 4 5 24 MeK MeQ D MeQ F4COO TMe I F4aa MeNal2 G F41Me4Pyz MeC NH225 MeK MeQ D MeA4paa F4COO TMe I F4aa MeNal2 G F41Me4Pyz MeC NFh 26 MeQ MeQ D MeK F4COO I I F4aa MeNal2 G F4J Me4Pyz MeC NH227 MeQ MeQ D MeQ Yae I I F4aa MeNal2 G F41Me4Pyz MeC NH228 MeQ MeQ D MeQ F4COO I I Yae MeNal2 G F41Me4Pyz MeC NH229 MeK MeQ Hgn MeQ F4COO TMe I Y MeNal2 G F4J Me4Pyz MeC NIG 30 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC NFL 31 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC de NFL 32 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC E NIL 33 MeK(de) Mel D MeQ F4COO I I F4aao MeNaI27N G 3Py6Ph MeC NFL 34 MeK(H) Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC NIL 35 MeK MeQ D MeQ F4COO TMe I F4aao MeNaI27N G 3Py6Ph MeC NFL 36 MeQ MeHseMe D MeQ F4COO TMe I F4aao MeNal27N G MeC NH2F41Me4PyzYaeCO37 MeQ MeHseMe D MeQ F4COO TMe Ipipzaa MeNal2 G 3Py6Ph MeC NH2F4amCO38 MeQ MeHseMe D MeQ F4COO TMe I MeNal2 G 3Py6Ph MeCpipzaa NH239 MeQ MeHseMe D MeQ F4COO TMe I F4u MeNal2 G 3Py6Ph MeC NH2F4aao40 MeQ MeHseMe D MeQ F4COO TMe I MeNal2 G 3Py6Ph MeCpipzaa NH241 MeK(df) Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC NH242 MeK(datb) Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC NH243 MeA MeQ D MeQ I I MeNal2 G 3Py6Ph MeC NH2F4COO F4COO44 MeA MeHseMe D MeQ F4COO TMe I Yae MeNal2 G 3Py6Ph MeC NH245 MeK MeHseMe D MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC NIL MeKCO MeDapCO46 MeK TMe I MeNal27N G 3Py6Ph MeCpipzaa Dpipzaa F4COO F4aao NFLAttorney Docket No. 01277-0089-00PCT-RYZPeptide Sequence?rom residue position 1 to residue position 15, if present)SEQ 1 1 11 2 3 4 5 6 7 8 9 10 11 12 Term ID No. 4 5MeKCO MeDapCO47 MeK D 3Py6NHaa TMe I F4aao MeNal27N G 3Py6Ph MeC NH pipzaa pipzaa2MeKCO MeKCO YaeCOpip48 MeK D F4COO I MeNal27N G 3Py6Ph MeCpipzaa pipzaa TMe zaa NH2MeKCO MeKCO F4aaopipz49 MeK D F4COO TMe I MeNaI27N G 3Py6Ph MeCpipzaa pipzaa aa NH2MeDapCO MeDapCO50 MeHseMe D F4COO TMe I Yae MeNal2 G 3Py6Ph MeCpipzaa pipzaa NH2MeDapCO MeDapCO51 MeHseMe D 3Py6NHaa TMe I Yae MeNal27N G 3Py6Ph MeCpipzaa pipzaa NH2MeDapCO52 MeK MeHseMe D TMe I F4aao MeNal27N G 3Py6Ph MeCpipzaa F4COO NH2MeDapCO53 MeK MeHseMe D 3Py6NHaa TMe I F4aao MeNal27N G 3Py6Ph MeCpipzaa NH2MeDapCOpi MeDapCO54 MeHseMe D TMe I Yae MeNal27N G 3Py6Ph MeCpzaa pipzaa F4COO NH2MeKCO MeDapCO55 MeHseMe D F4COO TMe I Yae MeNal27N G 3Py6Ph MeCpipzaa pipzaa NH2MeKCO56 MeA D MeY F4COO TMe I Yae MeY G 3Py6Ph MeCpipzaa NH2MeKCO57 MeA MeY D F4COO TMe I Yae MeY G 3Py6Ph MeCpipzaa NH2MeKCO58 MeHseMe D MeQ F4COO TMe I Y MeNaI27N G 3Py6Ph MeCpipzaa NH2MeKCO59 MeHseMe D MeQ F4COO S3RE1 I Y MeNal27N G 3Py6Ph MeCpipzaa NH2P EG60 MeKAc Mel D MeQ F4COO I I Y MeNaI27N G 3Py6Ph MeC G K1 NH20 c61 MeK MeHseMe D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC NH262 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC NH263 MeK MeHseMe D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC NH264 MeK Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC NH265 MeK MeQ Hgn MeQ F4COO TMe I F4aa MeNal2 G F41Me4Pyz MeC NH2Attorney Docket No. 01277-0089-00PCT-RYZPeptide Sequence?rom residue position 1 to residue position 15, if present)SEQ 1 1 1 ID No. i 2 3 4 5 6 7 8 9 10 11 12 4 5 Term 66 MeA MeY D Y TMe I Y MeNal2 G 3Py6Ph MeC NH267 MeA S D Y I I Y MeNal2 G 3Py6Ph MeC NH268 MeA S W5N Y I I Y MeNal2 G 3Py6Ph MeC NH269 MeA Me3Py D Y all I Y MeNal2 G 3Py6Ph MeC NH270 MeA S Q Y I I Y MeNal2 G 3Py6Ph MeC NH271 MeA TMe D Y Cle I Y MeNal2 G 3Py6Ph MeC NH272 MeK MeHseMe D MeQ F4COO I I Y MeNal27N G 3Py6Ph MeC NH2Table B. Example conjugates of the present disclosure containing a chelated cold Lutetium (Lu-175) (12mer cyclic peptides). "‘Term” refers to the functional group at the C-terminus.Conjugate SEQ ID1 2 3 4 5 6 7 8 9 10 11 12 13 Ter ID NO.MeKLu-C-1 240 Mel D MeQ F4COO I I Y MeNal27N G 3Py6Ph MeC -NH (DOTA-Lu)MeKLu-C-21 241 MeHseMe D MeQ F4COO I I F4aa MeNal2 G 3Py6Ph MeC(DOTA-Lu) -NH MeKLu-C-22 242 MeHseMe D MeQ F4COO I! F4aa MeNal2 G F41Me4Pyz MeC(DOTA-Lu) -NH MeKLu-C-24 243 MeQ D MeQ F4COO TMe I F4aa MeNal2 G F41Me4Pyz MeC(DOTA-Lu) -NH YaeLu-C-28 244 MeQ MeQ D MeQ F4COO I I MeNal2 G F41Me4Pyz MeC(DOTA-Lu) -NH MeKLu-C-26 MeQ MeQ D (DOTA- F4COO I I F4aa MeNal2 G F41Me4Pyz MeC -NHAttorney Docket No. 01277-0089-00PCT-RYZConjugate SEQ ID1 2 3 4 5 6 7 8 9 10 11 12 13 Ter ID NO.MeKLu-C-30 246 Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC -NH (DOTA-Lu)MeKLu-C-31 247 Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC de -NH (DOTA-Lu)MeKLu-C-32 248 Mel D MeQ F4COO TMe!(DOTA-Lu) F4aao MeNal27N G 3Py6Ph MeC E. -NH Lu-C-33 MeK(de)249 Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC -NH (DOTA-Lu)MeK(H)Lu-C-34 250 Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC(DOTA-Lu) -NH MeKLu-C-35 251 (DOTA-Lu) MeQ D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC -NH YaeLu-C-44 252 MeA MeHseMe D MeQ F4COO TMe I MeNal2 G 3Py6Ph MeC -NH (DOTA-Lu)MeKLu-C-45 253 (DOTA-Lu) MellseMe D MeQ F4COO TMe! Y MeNal27N G 3Py6Ph MeC -NH MeK(df)Lu-C-41 254 Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC(DOTA-Lu) -NH MeK(datb)Lu-C-42 255 Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC(DOTA-Lu) -NH MeKLu-C-64 256 Mel D MeQ F4COO I I F4aao MeNal27N G 3Py6Ph MeC(DOTA-Lu) -NH MeKLu-C-62 257 Mel D MeQ F4COO TMe! y MeNal27N G 3Py6Pb MeC -NF (DOTA-Lu)MeKLu-C-72 258 MeHseMe D MeQ F4COO I! Y MeNal27N G 3Py6Ph MeC(DOTA-Lu) -NH MeKLu-C-63 259 MeHseMe D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC(DOTA-Lu) -NHAttorney Docket No. 01277-0089-00PCT-RYZTable 1. Example peptide sequences with avidity to GPC3, from N -terminal amino acid position 1 to amino acid position 12 (Xi to X12 in Formula I, respectively)SEQ ID NO 1 7 3 4 5 6 7 8 9 10 11 12 76 MeK Mel D MeQ F4COO TMe TMe Y MeNal27N G 3Py6Ph MeC 80 MeK Mel D MeQ F4COO TMe I Cha MeNal27N G 3Py6Ph MeC 81 MeK Mel D MeQ F4COO TMe I F3OH MeNal27N G 3Py6Ph MeC 85 MeK Mel MeD MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 86 MeK Mel D MeQ MeF4COO TMe I Y MeNal27N G 3Py6Ph MeC 87 MeK Mel D MeQ F4COO TMe I Y MeNal27N MeG 3Py6Ph MeC 105 MeK Mel S MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 106 MeK Mel T MeQ F4COO TMe I Y MeNal27N G 3Py6Pb MeC 107 MeK Mel D MeQ F4COO TMe V Y MeNal27N G 3Py6Ph MeC 108 MeK Mel D MeQ F4COO TMe L Y MeNal27N G 3Py6Ph MeC 137 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Pyrazoll MeC 226 MeK Mel A MeQ F4COO TMe I F4aao MeNal27N G 3Py6PyrazoIl MeC 231 MeK Mel A MeQ F4COO TMe I F4aao MeNal27N G F41Me4Pyz MeC 501 MeK Mel Hgn MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC 502 MeK MeQ A MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC 503 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC 504 MeK Mel A MeQ F4COO TMe I F4COO MeNal27N G 3Py6Pyrazoll MeC 505 MeK Mel A MeQ F4COO TMe I F4aa MeNal27N G 3Py6Pyrazoll MeC 506 MeA Mel D MeQ F4COO TMe I 14a; 10 MeNal27N G 3Py6PyrazoIl MeC 507 MeA Mel D MeQ F4COO TMe I F4aa MeNal27N G 3Py6PyrazoIl MeC 508 MeA Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll C 509 MeK Mel A MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC 510 MeK Mel (S)Mor(2CO) MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID NO 1 2 3 4 5 6 7 8 9 10 11 12 511 MeK A F4(CONMel MeQ F4COO TMe I MeNal27NMeOH) G 3Py6Pyrazoll MeC 512 MeK Mel diMeDap MeQ F4(SO3H) TMe I F4aa MeNal27N G 3Py6Pyrazoll MeC 513 F4CONHMeK Mel A MeQ F4COO TMe I MeNal27N G 3Py6Pyrazoll MeC Me514 MeK F4CONMMel A MeQ F4COO TMe I MeNal27Ne2 G 3Py6Pyrazoll MeC 515 MeK Mel Hva MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC 516 MeK Mel N MeQ TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC F4COO517 MeK (PyrrCOO)Mel A MeQ I MeNal27NA TMe F4aao G 3Py6Pyrazoll MeC 518 MeKA I (PyrrCOO MeNal27N Mel MeQ TMe G MeC F4COO 3Py6Pyrazoll)AMeK 519 A I MeNal27N Mel MeQ F4(SO3H) G 3Py6Pyrazoll MeC TMe F4aaMeK 3Py6(4MePyr 520 A I MeNal27N Mel MeQ F4COO TMe F4aao G MeC azoll)MeK 3Py6(3MePyr521 A I MeNal27N Mel MeQ TMe F4aao G MeC F4COO azol 1)Table 2. Example peptide sequences with avidity to GPC3, from N -terminal amino acid position 1 to amino acid position 12 (Xi to X12 in Formula I, respectively), and amino acid position 13 (X13 in Formula I) if presentSEQ ID 2 3 1 4 5 6 7 8 9 10 11 12 13 NO.90 MeE D MeK I Y MeNal27N 3Py6Ph Mel TMe G MeC F4COO91 MeE D MeK I Y MeNal27N MeQ F4COO TMe G 3Py6Ph MeC 93 MeK D I MeNal27N 3Py6Ph MeQ MeQ F4COO TMe F4aao G MeC 94 K I MeNal27N MeQ Mel MeQ TMe G 3Py6Ph MeC F4COO F4aaoAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID1 2 3 4 5 6 7 8 9 10 11 12 13 NO.97 MeQ Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC dK 109 MeK Mel D MeQ F4COO TMe I F4F MeNal27N G 3Py6Ph MeC 126 MeK Mel D MeQ F4COO TMe I Aph MeNal27N G 3Py6Ph MeC 142 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6O4piplMs MeC 143 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6O4piplAc MeC 144 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6O4tlip MeC 147 MeK Mel D MeQ F4COO alTMe I F4aao MeNal27N G 3Py6Ph MeC 148 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N da 3Py6Pb MeC 149 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N ds 3Py6Ph MeC 150 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G F43Py5H MeC 151 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N G F44Pdo MeC 152 MeQ Mel K MeQ F4COO TMe I F4u MeNal27N G 3Py6Ph MeC 153 MeQ Mel K MeQ Y TMe I YaeCOpi MeNal27N G 3Py6Ph MeC pzaa160 MeK Mel D MeQ F4COO TMe I F4aao MeNal27N da F43Py5H MeC 161 MeK Mel Hgn MeQ Y TMe I F4u MeNal27N da F43Py5H MeC 162 MeK Mel Hgn MeQ F4COO TMe I F4u MeNal27N da F43Py5H MeC 163 MeQ Mel Hgn MeK F4COO TMe I F4u MeNal27N da F43Py5H MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID1 2 3 4 5 6 7 8 9 10 11 12 13 NO.164 MeK Mel Hgn MeQ Y TMe I F4aao MeNal27N da F43Py5H MeC 165 MeK Mel Hgn MeQ F4COO TMe I F4u MeNal27N da 3Py63Py5H MeC 166 MeQ Mel Hgn MeK F4COO TMe I F4u MeNal27N da 3Py63Py5H MeC 167 MeK Mel Hgn MeQ Y TMe I F4aao MeNal27N da 3Py63Py5H MeC 168 MeQ Mel Hgn MeQ F4COO TMe I F4u MeNal27N da 3Py61ap4pyz MeC 169 MeQ Mel Hgn MeQ F4COO TMe I F4u MeNal27N da F41apPyz MeC 170 MeK Mel Hgn MeQ F4COO TMe I F4u MeNal27N G 3Py63Py5H MeC 171 MeK Mel Hgn MeQ Y TMe I F4aao MeNal27N G 3Py63Py5H MeC 172 MeQ Mel Hgn MeK Y TMe I F4u MeNal27N da F43Py5H MeC 173 MeQ Mel Hgn MeK Y TMe I YaeCOpi MeNal27N da F43Py5H MeC pzaa174 MeQ Mel Hgn MeK Y TMe I YaeCOpi MeNal27N da 3Py63Py5H MeC pzaa175 MeK Mel A MeQ F4COO TMe I F4u MeNal27N da 3Py6Ph MeC 176 MeK Mel A MeQ F4COO TMe I F4u MeNal27N G 3Py6Ph MeC 177 MeK Mel A MeQ F4COO TMe I Y MeNal27N da 3Py6Ph MeC 178 MeK Mel Hgn MeQ F4COO TMe I F4u MeNal27N da 3Py6Ph MeC 179 MeK Mel Hgn MeQ F4COO TMe I Y MeNal27N da 3Py6Ph MeC 180 MeK Mel Hgn MeQ F4COO I I F4u MeNal27N da 3Py6Ph MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID1 2 3 4 5 6 7 8 9 10 11 12 13 NO.182 MeK Mel Hgn MeQ F4COO I I Y MeNal27N da 3Py6Ph MeC 185 MeA Mel A MeK F4COO I I Y MeNal27N G 3Py6Ph MeC 186 MeA Mel Hgn MeK F4COO I I Y MeNal27N da 3Py6Ph MeC 187 MeA Mel A MeK F4COO I I Y MeNal27N da 3Py6Ph MeC 188 MeA Mel Hgn MeK F4COO TMe I Y MeNal27N da 3Py6Ph MeC 189 MeA Mel A MeK F4COO TMe I Y MeNal27N da 3Py6Ph MeC 190 MeA Mel Hgn MeQ F4COO TMe I Y MeNal27N da 3Py6Ph MeC dk 191 MeA Mel Hgn MeQ F4COO TMe I Y MeNal27N G 3Py6Pb MeC dk 192 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py63Py MeC 193 MeK Mel D MeQ F4COO TMe I Y MeNal27N G F42Py MeC 194 MeK Mel D MeQ F4COO TMe I Y MeNal27N G F44Py MeC 195 MeE Mel D MeQ 4Py TMe I F4aao MeNal27N G 3Py6Ph MeC 196 MeA MeE D MeQ 3Py6NH2 'TMe I F4fl30 MeNal27N G 3Py6Ph MeC 197 MeA Mel E MeQ F4COO TMe I 3Py6NEI2 MeNal27N G 3Py6Ph MeC 198 MeA Mel D MeE F4COO TMe I 4Py MeNal27N G 3Py6Ph MeC 199 MeA Mel D MeQ F4COO TMe I F4aao MeF3Me4C G 3Py6Ph MeC 200 MeA Mel D MeQ F4COO TMe I F4aao MeF34dOMe G 3Py6Ph MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID1 2 3 4 5 6 7 8 9 10 11 12 13 NO.201 CrpG Mel D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC 202 MeA Mel D CrpG F4COO TMe I F4fl30 MeNal27N G 3Py6Ph MeC 203 MeA Mel D MeQ F4COO TMe TMe F4aao MeNal27N G 3Py6Ph MeC 204 MeA Mel D MeQ F4COO TMe I F4aao MeW7N G 3Py6Ph MeC 205 MeA Mel D MeQ F4COO TMe I F4aao MeNal27N ds 3Py6Ph MeC 206 MeA Mel D MeQ F4COO TMe I F4aao MeNal27N dp 3Py6Ph MeC 207 MeA Mel D MeQ 3Py6COO TMe I F4aao MeNal27N G 3Py6Ph MeC 208 MeA Mel D MeQ F4COO TMe I F4aao MeNal27N G Bph4C MeC 209 MeA Mel D MeQ F4COO TMe Gcpe F4aao MeNal27N G 3Py6Ph MeC 210 MeA Mel D MeQ F4COO L I F4aao MeNal27N G 3Py6Ph MeC 211 MeA Mel D MeQ F4COO TMe Eva F4aao MeNal27N G 3Py6Pb MeC 212 MeA MeK D MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC 213 MeA Mel K MeQ F4COO TMe I F4aHO MeNal27N G 3Py6Ph MeC 214 MeKAc Mel D MeQ F4COO I I Y MeNal27N G 3Py6Ph MeC dkAttorney Docket No. 01277-0089-00PCT-RYZTable 3. Example peptide sequences with avidity to GPC3, from N -terminal amino acid position 1 to amino acid position 12 (Xi to X12 in Formula I, respectively)SEQ ID1 2 3 4 5 6 7 8 9 10 11 12 NO.88 MeK MeQ D MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 98 MeK Mel Hgn MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeCTable 4. Example peptide sequences with avidity to GPC3, from N -terminal amino acid position 1 to amino acid position 12 (Xi to X12 in Formula I, respectively)SEQ ID1 2 3 4 5 6 -7 8 9 10 11 12 NO.89 MeA Mel D MeK F4COO TMe I Y MeNal27N G 3Py6Ph MeC 92 MeK Mel D MeQ F4COO TMe I Y MeNal27N G F41Me4Pyz MeC 95 MeQ Mel D MeK F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC 96 MeQ Mel D MeQ F4COO TMe I Yae MeNal27N G 3Py6Ph MeC 114 MeK Mel Hgn MeQ F4COO TMe I F4U MeNal27N G 3Py6Ph MeC 115 MeK Mel Hgn MeQ F4COO TMe I YaeCOpipzaa MeNal27N G 3Py6Ph MeC 116 MeK MeHseMe Hgn MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 117 MeK MeKCOpipzaa Hgn MeQ F4COO TMe I YaeCOpipzaa MeNal27N G 3Py6Ph MeC 127 MeK Mel D MeQ F4COO TMe I F4U MeNal27N G 3Py6Ph MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID1 2 3 4 5 6 7 8 9 10 11 12 NO.140 MeK Mel Hgn MeDapC F4COO TMe 1 Y MeNal27N G 3Py6Ph MeC Opipzaa141 MeK MeKCOpipzaa Hgn MeDapC F4COO TMe I Y MeNal27N G 3Py6Ph MeC Opipzaa145 MeK MellseMe Hgn MeQ F4COO TMe I F4u MeNal27N G 3Py6Ph MeC 146 McK Mel Hgn MeDapC F4COO TMe I F4u MeNal27N G 3Py6Ph MeC Opipzaa154 MeQ Mel Hgn MeK F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC 155 MeQ Mel Hgn MeK Y TMe I F4aao MeNal27N G 3Py6Ph MeC 156 MeQ Mel Hgn MeK F4COO TMe I F4u MeNal27N G 3Py6Ph MeC 157 MeQ Mel Hgn MeK Y TMe I YaeCOpipzaa MeNal27N G 3Py6Ph MeC 158 MeQ Mel Hgn MeQ F4COO TMe I Yae MeNal27N G 3Py6Ph MeC 159 MeQ Mel D MeQ Y TMe I Yae MeNal27N G 3Py6Ph MeC 181 MeK Mel Hgn MeQ F4COO I I F4u MeNal27N G 3Py6Ph MeC 183 MeK Mel Hgn MeQ F4COO I I Y MeNal27N G 3Py6Ph MeC 184 MeA Mel Hgn MeK F4COO 1 1 Y MeNal27N G 3Py6Ph MeCTable 5, Example conjugates of the present disclosure comprise a metal chelator and sequence of amino acids from N -terminal position 1 to position 12 (X] to X12 in Formula I, respectively), and position 13 (Xis in Formula I) if present, as shown in the table below. Each cysteine side chain of position 12 is covalently linked to the N -terminus of amino acid 1 via -CH2-CO-, thereby forming a cyclic peptide.Attorney Docket No. 01277-0089-00PCT-RYZConjugateConjugate SEQ Peptide SEQ 1 2 3 4 5 6 '7 8 9 10 11 12 c- ID ID ID NO. terminus NO:C-76 527 76 MeKfDO Me D Me T TF4 Y MeNal2 MeTA) I COO0 Me Me 7N G 3Py6PhC NH2C-80 MeKfDO T531 80 Me D Me MeNal2 MeT F4COO I Cha G 3Py6PhA) I Q Me 7N C NH2C-81 T Me53 MeKfDO Me Me Nal22 81 D Me F4COO I F3 3Py6PhTA) I OH0 Me 7N G C NHz T M C-85 MeKfDO Me M eNal2536 85 MeD e 1 Y G MeTA) I F4COO 7N 3Py6PhMe NHz 0 CC-86 MeKfDO Me Me M T537 86 D eF4CO I Y MeNal2 Me NHz TA) I 7 G 3Py6PhN O Me C 0T C-87 MeKfDO Me Me MeNal2 Me Me NHz 538 D I Y 3Py6Ph 87 F4COO TA) I 7N Me G C QT MeNal2 C-105 Me Me Me MeKfDO NHz 556 105 I Y 3Py6Ph S F4COO G TA) I 7N Me C 0C-106 T MeNal2 MeKfDO Me Me Me NHz 557 106 T 1 Y G 3Py6Ph F4COO TA) I 7N Me C 0T C-107 MeKfDO Me Me MeNal2 Me NHz 558 107 D Y F4COO V G 3Py6Ph TA) I 7N Me C QT C-108 MeKfDO Me Me MeNal2 Me NHz 559 108 D L Y F4COO G 3Py6Ph TA) I 7N Me C 0T MeNal2 C-137 MeKfDO Me Me Me NHz 588 137 D I Y F4COO G 3Py6Py razol 1 I 7N TA) Me C QC-226- T MeKfDO Me Me MeNal2 Me NHz 591 226 A 1 G 3Py6Pyrazoll F4COO F4aao DO'IA TA) 1 7N Me C QT C-226- MeKfNO Me Me MeNal2 Me NHz 592 226 A I F4COO F4aao G 3Py6Py razol 1 NOTA TA) I 7N Me C 0('■231 T MeKfDO Me Me MeNal2 Me NHz 593 231 A I F4COO G F41Me4Pyz F4aao TA) I 7N Me C 0C-501 T MeNal2 MeKfDO Me Me Me NHz 594 501 Hgn I F4COO F4aao G 3Py6Py razol 1 TA) I 7N Me C QC502 T MeNal2 MeKfDO Me Me Me NHz 595 502 A I F4COO F4aao G 3Py6Pyrazoll TA) 7N Me C Q QAttorney Docket No. 01277-0089-00PCT-RYZConjugateConjugate SEQ Peptide SEQ 1 2 3 4 5 6 '7 8 9 10 11 12 c- ID ID ID NO. terminus NO:C-503 596 503 MeKCDO Me D Me TF4 I MeNal2 Me NH2TA) I COO F4aao G 3Py6PyrazollQ Me 7N CC-504 597 504 MeK(DO Me A Me T MeNal2 Me NH2T F4COO IA) I F4COO 7N G 3Py6PyrazollQ Me CC-505598 505 MeKCDO Me T MeNalA Me 2I MeF NHz4COO F4aa G 3Py6Pyrazoll TA) I 7N Me C 0C-506- T MeNal2 Me Me Me PEG2CDO 599 506 D I PEG2(DO MeA G 3Py6Pyrazoll F4COO F4aao I 7N TA) Me C Q TA)T C-507 Me Me MeNal2 Me PEG2(DO 601 507 MeA D I F4COO F4aa G 3Py6Pyrazoll I 7N TA) Me C 0C-506- T Me Me MeNal2 Me PEG4(DO 600 506 MeA D I PEG4(DO F4COO F4aao G 3Py6Pyrazoll I 7N TA) Me C Q TA)C-508 T MeNal2 Me Me PEG2(DO 602 508 MeA D I F4COO F4aao G 3Py6Py razol 1 c I 7N TA) Me QC-509 MeK(PE NHz T MeNal2 Me Me Me 603 509 G2- A I G 3Py6Pyrazoll F4COO F4aao I 7N Me C Q DOTA)C-510 T MeNal2 MeK(DO Me (S)Mor(2 Me Me NHz 604 510 I F4COO F4aao G 3Py6Py razol 1 TA) I 7N CO) Me C 0T F4CCONM C-511 MeKCDO Me Me MeNal2 Me NH2605 511 A I F4COO G 3Py6Pyrazoll TA) I eOH) 7N Me C QF4CSO3 T MeNal2 NHz C-512 MeKCDO Me Me Me 606 512 I diMeDap F4aa G 3Py6Py razol 1 TA) I 7N Me C H) 0T F4CONHM MeNal2 C-513 MeK(DO Me Me Me NHz 607 513 A I G 3Py6Pyrazoil F4COO TA) I 7N Me e C QC-514 T MeNal2 Me Me F4CONMe Me MeK(DO NHz 608 514 A I F4COO G 3Py6Py razol 1 TA) I 2 7N Me C 0T C-515 MeK(DO Me Me MeNal2 Me NHz 609 515 I Hva F4COO F4aao G 3Py6Pyrazoll TA) I 7N Me C QT C-516 MeKCDO Me Me MeNal2 Me NHz 610 516 N I F4COO F4aao G 3Py6Pyrazoll TA) I 7N Me C QAttorney Docket No. 01277-0089-00PCT-RYZConjugateConjugate SEQ Peptide SEQ 1 2 3 4 5 6 '7 8 9 10 11 12 C- ID ID ID NO. terminus NO:C-517 611 517 MeKfDO Me A Me (PyrrCO T I MeNal2F4a Me NH2TA) I ao 7N G 3Py6PyrazollQ b)A Me CC-518 T MeNal2612 518 MeK(DO Me A Me (PyrrCOO) Me F4COO ITA) I Q Me A 7N G 3Py6Pyrazoll NH2CC-519 MeK(D F4(SO3 T MeNal2 NHz 613 519 O Me A Me I MeTA) I F4aa 7N G 3Py6PyrazollH Me C) 0C-520 T MeNal2 3Py6(4MePvr NH2MeK(DO Me Me Me 614 520 A I G F4COO F4aao TA) I 7N Me azoll) C 0C -521 T 3Py6(3MePyr NH2MeK(DO Me Me MeNal2 Me 615 521 A I F4COO F4aao G TA) I 7N Me azoll) C QPEG2(D0TA) is attached to the C-terminus of the peptide through an amide bond as follows (where the initial N(H) is the N(H) of the amide bond): [position 12]- N(H)-(CH2CH2O)2-CH2CH2-N(H)-[DOTA]; and PEG4(DOTA) is attached to the C-terminus of the peptide through an amide bond as follows (where the initial N(H) is the N(H) of the amide bond): [position 12]-N(H)-(CH2CH2O)4-CH2CH2-N(H)-[DOTA].Table 6, Example conjugates of the present disclosure comprise a metal chelator and sequence of amino acids from N -terminal position 1 to position 12 (Xj to X] 2 in Formula I, respectively), and position 13 (Xi3in Formula I) if present, as shown in the table below. Each cysteine side chain of position 12 is covalently linked to the N -terminus of amino acid 1 via -CH2-CO-, thereby forming a cyclic peptide.PeptidConjuga C- e SEQ 1 Conjuga 1 2 3 4 5 6 7 8 9 11 12 13 termin te SEQ ID 0 te IDID NO: us NO.C-90 541 MeK(DOT TM 3Py6P NH2F4CO MeNal27 Me 90 MeE D I Y Mel G N h 0 e C A)C-91 542 MeK(DOT TM MeNal27 NH23Pv6P Me F4CO 91 MeE D I Y MeQ G N h 0 e C A)Attorney Docket No. 01277-0089-00PCT-RYZPeptidConjuga C- Conjuga e SI iQ 1te SEQ 1 2 3 4 5 6 7 8 9 11 12 13 termln te ID ID 0ID NO: us NO.C-93 543 MeKfDOT F4CO TM F4aa MeNal27 3Py6P93 MeQ D MeQ I Me NH2A) 0 e 0 N G h CC-94 544 K(DOT F4CO IM F4aa MeNal27 3Pv6P Me NH294 I MeQ Mel MeQ G A) N 0 e 0 h CC-97 548 TM 3Py6P dK(DOT NH2F4CO F4aa MeNal27 Me 97 D I MeQ Mel MeQ G N 0 e 0 h C A)MeK(DOT TM MeNal27 560 F4CO 3Py6P Me NH2C-109 109 D I F4F Mel MeQ G A) N 110 e CMeNal27 3Py6P C-126 577 MeKfDOT TM NH2F4CO Me D I Aph Mel MeQ G 126 N h 0 C e A)Table 7. Example conjugates of the present disclosure comprise a metal chelator and sequence of amino acids from N -terminal position 1 to position 12 (X] to X12 in Formula I, respectively), as shown in the table below. Each cysteine side chain of position 12 is covalently linked to the N -terminus of amino acid 1 via -CH2-CO-, thereby forming a cyclic peptide.Conjugate Conjugate SEQ ID Peptide SEQ ID 3 1 2 4 5 6 7 8 9 10 11 12 C-te minus ID NO. NO.C-88 539 88 MeK(DOTA) D 1 Y MeNal27N NH2MeQ MeQ F4COO TMe G 3Py6Ph MeCC-98 549 98 MeK(DOTA) Hgn I Y MeNal27N NH2Mel MeQ F4COO TMe G 3Py6Ph MeCTable 8. Example conjugates of the present disclosure comprise a metal chelator and sequence of amino acids from N -terminal position 1 to position 12 (Xi to X12 in Formula I, respectively), as shown in the table below. Each cysteine side chain of position 12 is covalently linked to the N -terminus of amino acid 1 via -CH2-CO-, thereby forming a cyclic peptide.Attorney Docket No. 01277-0089-00PCT-RYZConjugat Conjugat Peptide ID e SEQ e SEQ3 4 7 11 2 5 6 8 9 11 12 c- ID NO: ID 0 terminus NO.C-89 540 MeK(DOT89 MeA F4CO TM MeNal27 MeMel D I YA) 0 e N G 3Py6PhC NH2543 MeK(DOT TM MeNal27 F41Me4Pyz C-92 Me F4CO 92 D I Y NH2Mel MeQ G N 0 e C A)C-95 546 MeK(DOT TM F4CO MeNal27 Me 95 D I 3Py6Ph NH2MeQ Mel F4aao G N 0 e C A)TM MeNal27 C-96 547 F4CO Me 96 D I Yae(DOTA) 3Py6Ph NH2MeQ Mel MeQ G N 0 e CC-114 565 TM McK(DOT F4CO MeNal27 Me Hg 114 I 3Py6Ph NH2Mel MeQ F4U G n N 0 e C A)566 Hg TM C-115 MeK(DOT F4CO YaeCOpipz MeNal27 Me 115 I 3Py6Ph NH2Mel MeQ G n N 0 e aa C A)567 MeK(DOT Hg TM MeNal27 C-116 Me F4CO I Y 3Py6Ph NH2MeHseMe MeQ G 116 n N 0 e C A)568 MeKCOpipz TM YaeCOpipz C-117 MeK(DOT F4CO MeNal27 Me Hg I 3Py6Ph NH2MeQ G 117 n N aa 0 e aa C A)578 MeKfDOT TM MeNal27 C-127 F4CO Me 127 D I 3Py6Ph NH2Mel MeQ F4U G N 0 e C A)Table 9A. Example peptide sequences with avidity to GPC3, from N -terminal amino acid position 1 to amino acid position 12 (Xi to X12in Formula I, respectively)1 5 2 3 4 6 7 8 9 10 11 12 SEQ ID NO73 MeA D I Y MeNal27N 3Py6Ph MeK MeQ F4COO TMe G MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID NO. 1 2 3 4 5 6 7 8 9 10 11 12 74 MeK MeTMe D MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 75 MeK Mel D MeQ F4COO TMe A Y MeNal27N G 3Py6Pb MeC 77 MeK Mel D MeQ F4COO TMe I Y MeNal27N da 3Py6Ph MeC 78 MeK Mel D MeQ F4COO TMe I Y MeNal27N ds 3Py6Ph MeC 79 MeK Mel D MeQ F4COO TMe I A MeNal27N G 3Py6Pb MeC 82 MeK Mel D MeA F4COO TMe I Y MeNal27N G 3Py6Ph MeC 83 MeK Mel D MeQ F4COO A I Y MeNal27N G 3Py6Ph MeC 84 MeK Mel A MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 99 MeK Mel D MeQ F4COO TMe I Y MeNal27N G Phe(4-(3-Py)) MeC 100 MeK Mel D MeQ F4COO TMe I Y MeNal27N G Phe(4-(4-Py)) MeC 101 MeK Mel D MeQ F4COO TMe I Y MeNal27N G Phe(4-(2-Py)) MeC 102 MeK Mel D MeQ F4COO TMe I Y MeNal27N G Phe35N4Ph MeC 103 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py(6-(3-Py)) MeC 104 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py(6-(4-Py)) MeC 110 MeK Mel D MeQ F4COO TMe I Y MeNal27N dv 3Py6Ph MeC 111 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py(6-(2-Py)) MeC 112 MeK Mel D MeQ F4COO TMe I Y Me(7Me)6inda G 3Py6Ph MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID NO. 1 2 3 4 5 6 7 8 9 10 11 12 113 MeK Mel D MeQ F4COO TMe I Y Me(7Me)6indol G 3Py6Ph MeC 118 MeK Mel D MeQ F4COO TMe I Y Me6inda G 3Py6Pb MeC 119 MeK Mel D MeQ F4COO TMe I Y MeiW G 3Py6Ph MeC 120 MeK Mel A MeQ F4COO TMe I F4aao MeNal27N G 3Py6Ph MeC 121 MeK Mel G MeQ F4COO TMe I Y MeNal27N G 3Py6Pb MeC 122 MeK Mel da MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 123 MeK Mel Abu MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 124 MeK Mel V MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 125 MeK Mel diMeDap MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 128 MeK Mel D MeQ F4COO TMe I Y MeNal27N dt 3Py6Ph MeC 129 MeK Mel MeG MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 130 MeK Mel MeA MeQ F4COO TMe I Y MeNal27N G 3Py6Ph MeC 131 MeK Mel Dap MeQ F4COO TMe I Y MeNal27N G 3Py6Pb MeC 132 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Me MeC 133 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6(Pipl) MeC 134 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Imidaz 1 MeC 135 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py60xaz5 MeCAttorney Docket No. 01277-0089-00PCT-RYZSEQ ID NO. 1 2 3 4 5 6 7 8 9 10 11 12136 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Pipza MeC138 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Pyrazol3 MeC139 MeK Mel D MeQ F4COO TMe I Y MeNal27N G 3Py6Pyrroll MeCTable 9B. Example conjugates of the present disclosure comprise a metal chelator and sequence of amino acids from N -terminal position 1 to position 12 (Xi to X12 in Formula I, respectively), as shown in the table below. Each cysteine side chain of position 12 is covalently linked to the N -terminus of amino acid 1 via -CH2-CO-, thereby forming a cyclic peptide.PeptidConjugaConjuga e SEQ 1 C- te SEQ 1 2 3 4 5 6 7 8 9 11 12 te ID ID 0 terminus ID NO:NO.C-73 MeK(DOT Me F4CO TM Me524 73 MeA D I Y MeNal27N G 3Py6Ph NH A) Q 0 e C2(.’•74 MeK(DOT MeTM Me F4CO TM Me525 74 D I Y MeNal27N G 3Py6Ph NH A)2e Q 0 e CC-75 MeK(DOT Me F4C0 TM Me526 75 Mel D A Y MeNal27N G 3Py6Ph NH2A) Q 0 e CC-77 MeK(DOT Me F4CO TM d Me528 77 Mel D I Y MeNal27N 3Py6Ph NH2A) Q 0 e a C< -78 MeK(DOT Me F4CO TM Me529 78 Mel D I Y MeNal27N ds 3Py6Ph NH2A) Q 0 e CC-79 MeK(DOT Me F4CO TM Me530 79 Mel D I A MeNal27N G 3Py6Ph NH2A) Q 0 e CC-82 MeK(DOT Me F4CO TM Me533 82 Mel D I Y MeNal27N G 3Py6Ph NH2A) A 0 e CC-83 MeK(DOT Me F4CO Me534 83 Mel D A I Y MeNal27N G 3Py6Ph NH2A) Q 0 CAttorney Docket No. 01277-0089-00PCT-RYZPeptidConjugaConjuga e SEQ 1 C- te SEQ 1 2 3 4 5 6 7 8 9 11 12 te ID ID 0 terminus ID NO:NO.C-84 MeK(DOT Me F4CO TM Me535 84 Mel A I Y MeNal27N G 3Py6Ph NH A)20 0 e CC-99 MeK(DOT Me F4CO TM Phe(4-(3- Me550 99 Mel D 1 Y MeNal27N G NH A) Q 0 e y) C2P )C-100 MeK(DOT Me F4CO TM Phe(4-(4- Me551 100 Mel D I Y MeNal27N G NH2A) Q 0 c Pv)) CC-101 MeK(DOT Me F4CO TM Phe(4-(2- Me552 101 Mel D 1 Y MeNal27N G NH2A) Q 0 e Py)) CC-102 MeK(DOT Me F4CO TM Me553 102 Mel D I Y MeNal27N G Phe35N4Ph NH2A) 0 0 e CC-103 MeK(DOT Me F4CO TM 3Py(6-(3- Me554 103 Mel D I Y MeNal27N G NH2A) Q 0 e Py)) CC-104 MeK(DOT Me F4CO TM 3Py(6-(4- Me555 104 Mel D I Y MeNal27N G NH2A) Q 0 e Py)) CC-110 MeK(DOT Me F4CO TM d Me561 110 Mel D I Y MeNal27N 3Py6Ph NH2A) 0 0 e V CC-l l l MeK(DOT Me F4CO TM 3Py(6-(2- Me562 Ill Mel D 1 Y MeNal27N G NH2A) Q 0 e Py)) CC-112 MeK(DOT Me F4CO TM Me(7Me)6ind Me563 112 Mel D I Y G 3Py6Ph NH2A) Q 0 c a CC-113 MeK(DOT Me F4CO TM Me(7Me)6ind Me564 113 Mel D 1 Y G 3Py6Ph NH2A) Q 0 e ol CC-118 MeK(DOT Me F4CO TM Me569 118 Mel D I Y Me6inda G 3Py6Ph NH2A) Q 0 e CC-119 MeK(DOT Me F4CO TM Me570 119 Mel D I Y MeiW G 3Py6Ph NH2A) Q 0 e CC-120 MeK(DOT Me F4CO TM F4aa Me571 120 Mel A I MeNal27N G 3Py6Ph NH2A) Q 0 e 0 CC-121 MeK(DOT Me F4CO TM Me572 121 Mel G I Y MeNal27N G 3Py6Ph NH2A) Q 0 e CAttorney Docket No. 01277-0089-00PCT-RYZPeptidConjugaConjuga e SEQ 1 C- te SEQ 1 2 3 4 5 6 7 8 9 11 12 te ID ID 0 terminus ID NO:NO.C-122 MeK(DOT Me F4C0 TM Me573 122 Mel da I Y MeNal27N G 3Py6Ph NH A) Q 0 e C2( -123 MeK(DOT Me F4CO TM Me574 123 Mel Abu I Y MeNal27N G 3Py6Ph NH A) Q 0 e C2C-124 MeK(DOT Me F4CO TM Me575 124 Mel V I Y MeNal27N G 3Py6Ph NH2A) Q 0 c CC '-125 MeK(DOT diMeDa Me F4CO TM Me576 125 Mel 1 Y MeNal27N G 3Py6Ph NH2A) P Q 0 e CC-128 MeK(DOT Me F4C0 TM Me579 128 Mel D I Y MeNal27N dt 3Py6Ph NH2A) 0 0 e CC-129 MeK(DOT Me F4C0 TM Me580 129 Mel MeG I Y MeNal27N G 3Py6Ph NH2A) Q 0 e CC-130 MeK(DOT Me F4CO TM Me581 130 Mel MeA I Y MeNal27N G 3Py6Ph NH2A) Q 0 e CC-131 MeK(DOT Me F4C0 TM Me582 131 Mel Dap I Y MeNal27N G 3Py6Ph NH2A) 0 0 e CC-132 MeK(DOT Me F4CO TM Me583 132 Mel D I Y MeNal27N G 3Py6Me NI-I2A) Q 0 e CC-133 MeK(DOT Me F4CO TM Me584 133 Mel D I Y MeNal27N G 3Py6(PipI) NH2A) Q 0 c CC '-134 MeK(DOT Me F4CO TM 3Py6Imidaz Me585 134 Mel D 1 Y MeNal27N G NH2A) Q 0 e CC-135 MeK(DOT Me F4C0 TM Me586 135 Mel D I Y MeNal27N G 3Py60xaz5 NH2A) Q 0 e CC-136 MeK(DOT Me F4C0 TM Me587 136 Mel D I Y MeNal27N G 3Py6Pipza NH2A) Q 0 e CC-138 MeK(DOT Me F4CO TM 3Pv6Pyrazo Me589 138 Mel D I Y MeNal27N G NH2A) Q 0 e 13 CC-139 MeK(DOT Me F4C0 TM 3Py6Pyrrol Me590 139 Mel D I Y MeNal27N G NH2A) Q 0 e f CAttorney Docket No. 01277-0089-00PCT-RYZTable 20A. Example peptide sequences with avidity to GPC3, from N -terminal amino acid position 1 to amino acid position 12 (Xi to X12 in Formula I, respectively)SEQ ID NO. 1 2 3 4 5 6 7 8 9 10 11 12 C-terminus229 MeK Mel A MeQ F4COO TMe I F4aao MeNal27N G 3 Py 6(4MeIm idaz I ) MeC NH2227 MeK Mel A MeQ F4COO TMe I F4aao MeNal27N G 3Py6Imidazl MeC NH2522 MeK Me TMe A MeQ F4COO TMe I F4aao MeNal27N G 3Py6Pyrazoll MeC NH2523 MeK Mel A MeQ F4(SO3H) TMe I F4aao MeNal27N G 3Py6Pyrazol 1 MeC NH2Table 20B, Example conjugates of the present disclosure comprise a metal chelator and sequence of amino acids from N -terminal position 1 to position 12 (Xi to X12 in Formula I, respectively), as shown in the table below. Each cysteine side chain of position 12 is covalently linked to the N -terminus of amino acid 1 via -CH2-CO-, thereby forming a cyclic peptide.Conjugc- ate Peptide SEQ ID 1Conjugate ID 1 2 3 4 5 6 7 8 9 11 12 terminu SEQ ID NO. 0s NO.MeK(D0 Me TM F4a MeNal2 3Py6(4MeImi MeC-229 622 229 Mel A F4COO I G NH2 TA) Q e ao 7N dazl) C MeK(D0 Me TM F4a MeNal2 MeC-227 623 227 Mel A F4COO I G 3Py6Imidazl NH2 TA) Q e ao 7N C MeK(D0 MeT Me TM F4a MeNal2 MeC-522 624 522 A F4COO I G 3Py6Pyrazol 1 NH2TA) Me Q e ao 7N C MeK(D0 Me F4(SO3 TM F4a MeNal2 MeC-523 625 523 Mel A I G 3Py6Pyrazoll NH2 TA) Q H) c ao 7N CAttorney Docket No. 01277-0089-00PCT-RYZ

[0141] A peptide described herein can be cyclized (e.g, macrocyclized). Cyclization can be achieved less ideally via a single disulfide bond, or more ideally via a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, C — S — C bond, C — N — C bond, C=N — C bond, C=N — O bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, thioamide bond, or the like, but not limited to them. In some embodiments, the peptide is a cyclic peptide that is cyclized by a peptide bond, alkyl bond, alkenyl bond, ester bond, thioester bond, ether bond, thioether bond, phosphate ether bond, azo bond, C — N — C bond, C=N — C bond, C=N — O bond, amide bond, lactam bridge, carbamoyl bond, urea bond, thiourea bond, amine bond, or thioamide bond. In some embodiments, the cyclic peptide is cyclized by a thioether bond. In some embodiments, the cyclic peptide is cy clized via an oxime cyclization reaction. A cyclization of a peptide sometimes stabilizes the peptide structure and thereby enhance affinity for a target. The cyclization can occur between the N- and C-terminus, or it can occur between a terminal amino acid and a non-terminal amino acid. In some embodiments, the cyclization occurs between two non-terminal amino acids. In some embodiments, the peptide is cyclized via oxime cyclization. In some embodiments, the peptide is cyclized between cysteine and haloacyl. In some embodiments, the peptide comprises a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the N-terminus. In some embodiments, the peptide comprises a haloacetyl group (e.g., chloroacetyl or bromoacetyl) at the C-terminus. In some embodiments, the peptide comprises a Cys at the C-terminus. In some embodiments, the peptide comprises a Cys at the N-terminus, In some embodiments, the cyclization occurs via a thioether bond between Cys and a haloacetyl group. In some embodiments, the cyclization occurs between the N-terminus and the C-terminus of the peptide.

[0142] As amino acids for macrocyclization, for example, an amino acid having the following functional group A and an amino acid having a corresponding functional group B can be used (see Table 4A). Either the functional group A or the functional group B may be placed on the N-terminal side. The amino acid having the functional group A and the amino acid having the functional group B can each be an N-terminal amino acid or C-terminal amino acid or a non-terminal amino acid. In some embodiments, an amino acid having the functional group A is placed at the N-terminus. In some embodiments, an amino acid having the functional group A is placed at the C-terminus. In some embodiments, an amino acid having the functional group A is placed at a non-terminal amino acid. In some embodiments, an amino acid having the functional group B is placed at the N-terminus. In some embodiments, an amino acid having the functional group B is placed at the C-terminus. In some embodiments, an amino acid having the functional group B is placed at a non-terminal amino acid.Attorney Docket No. 01277-0089-00PCT-RYZTable 4A. Functional groups for cyclizationFunctional group A Functional group B 0s UH2 X-J HS— | (I)(I-A) (I-B) Xi is a halogen such as Cl. Br or IN(II) | — c= c —3(II-B) (II-A)Ar— CH2NH2(III)(III-A)Ar is substituted or unsubstituted aryl or heteroaryl (III-B)C c t t \Z(IV)(IV-A) (IV-B) Xi is a halogen such as Cl, Br or II — Ar — CH2— HS — (V) S (V-A)Xi is a halogen such as Cl, Br or I; Ar is substituted or (V-B) unsubstituted aryl or heteroarylO HS - (VI)(VI-A)(VI-B)(VII) c - SH(VII-A)(VII-B) ° (VIII) | — NH2(vni-A)(VIII-B)Attorney Docket No. 01277-0089-00PCT-RYZ(IX)(IX-A) (IX-B)

[00143] n some embodiments, the amino acid (I-A) in Table 4A can be, for example, a chloroacetylated amino acid. Exemplary chloroacetylated amino acids include N-chloroacetyl-L- alanine, N-chloroacetyl-L-phenylalanine, N-chloroacetyl-L -tyrosine, N-chloroacetyl-L -tryptophan. N-3-(2-chloroacetamido)benzoyl-L-phenylalanine, N-3-(2-chloroacetamido)benzoyl-L-tyrosine, N-3-(2-chloroacetamido)benzoyl-L-tryptophan, P-N-chloroacetyl-L-diaminopropanoic acid, y-N -chloroacetyl-L-diaminobutyric acid, o-N-chloroacetyl-L-ornithine, e-N-chloroacetyl-L-lysine, N-3-chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophane and D-amino acid derivatives corresponding thereto (for example, -Chloroacetyl -D-alanine, N-Chloroacetyl-D-phenylalanine, N-Chloroacetyl-D-tyrosine, and N-Chloroacetyl-D-tryptophan),

[0144] Examples of the amino acid (I-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, 2-amino-8- mercaptooctanoic acid, and amino acids obtained by protecting the SH group of these amino acids and then eliminating the protecting group, and D-amino acid derivatives corresponding thereto,

[0145] The cyclization method can be carried out, for example, according to the method described in Kawakami, T. et al., Nature Chemical Biology 5, 888-890 (2009); Yamagishi, Y. et al., ChemBioChem 10, 1469-1472 (2009); Sako, Y. et al.. Journal of American Chemical Society 130, 7932-7934 (2008); or W02008 / 117833.

[0146] In some embodiments, for example, the amino acid (II-A) is selected from propargylglycine, homopropargylglycine, 2-amino-6-heptynoic acid, 2-amino-7-octynoic acid, and 2-amino-8-nonynoic acid can be used. In addition, 4-pentynoylated or 5-hexynoylated amino acids can also be used.Examples of the 4-pentynoylated amino acids include N-(4-pentenoyl)-L-alanine, N-(4-pentenoyl)-L-phenylalanine, N-(4-pentenoyl)-L-tyrosine, N-(4-pentenoyl)-L-tryptophan, N-3-(4-pentynoylamido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4- pentynoylamido)benzoyl-L-tryptophan, P-N-(4-pentenoyl)-L-diaminopropanoic acid, y-N-(4-pentenoyl)-L-diaminobutyric acid, o-N-(4-pentenoyl)-L-omithine, and s-N-(4-pentenoyl)-L-lysine, and D-amino acid derivatives corresponding thereto.

[0147] In some embodiments, for example, the amino acid (II -B) is selected from azidoalanine, 2- amino-4-azidobutanoic acid, azidonorvaline, azidonorleucine, 2-amino-7-azidoheptanoic acid, and 2-amino-8-azidooctanoic acid can be used. In addition, azidoacetylated or 3-azidopentanoylated amino acids can also be used. Examples of the azidoacetylated ammo acids include N -azidoacetyl -L-alanine, N-azidoacetyl-L-phenylalanine, N-azidoacetyl-L-tyrosine, N-azidoacetyl-L-tryptophan, N-3- (4-pentynoylainido)benzoyl-L-phenylalanine, N-3-(4-pentynoylamido)benzoyl-L-tyrosine, N-3-(4-pentynoylamido)benzoyl-L-tryptophan, P-N -azidoacetyl-L-diaminopropanoic acid, y-N-azidoacetyl- L-di aminobutyric acid, a-N-azidoacetyl-L-ornithine, and g-N-azidoacetyl-L-lysine, and D-amino acidAttorney Docket No. 01277-0089-00PCT-RYZderivatives corresponding thereto.

[0148] The cyclization method can be performed, for example, according to the method described in Sako, Y, et al.. Journal of American Chemical Society 130, 7932-7934 (2008) or W02008 / 117833.

[0149] Examples of amino acid (III-A) include, but are not limited to, N-(4-aminomethyl-benzoyl)-phenylalanine (AMBF) and 4-3 -aminomethyltyrosine.

[0150] Examples of the amino acid (III-B) include, but are not limited to, -hydroxytryptophan (WoH). The cyclization method can be performed, for example, according to the method described in Yamagishi, Y et al., ChemBioChem 10, 1469-1472 (2009) or W02008 / 117833.

[0151] Examples of the amino acid (IV -A) include, but are not limited to, 2-amino-6-chloro-hexynoic acid, 2-amino-7-chloro-heptynoic acid, and 2-amino-8-chloro-octynoic acid.

[0152] Examples of the amino acid (IV -B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, amino acids obtained by protecting the SH group of these amino acids and then eliminating the protecting group, and D-amino acid derivatives corresponding thereto. The cyclization method can be performed, for example, according to the method described in WO2012 / 074129.

[0153] Examples of the amino acid (V-A) include, but are not limited to, N-3-chloromethylbenzoyl-L-phenylalanine, N-3-chloromethylbenzoyl-L-tyrosine, and N-3-chloromethylbenzoyl-L-tryptophane.

[0154] Examples of the amino acid (V-B) include, but are not limited to, cysteine, homocysteine, mercaptonorvaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid, and amino acids obtained by protecting the SH group of these amino acids and then eliminating the protecting group, and D-amino acid derivatives corresponding thereto.

[0155] The amino acids I-A to V-A and I-B to V-B can be introduced into the peptide in a known manner by chemical synthesis or translation and synthesis described herein. In some embodiments, the cyclization reaction comprises forming a thioether bond using an amino acid comprising a sulfanyl group, e.g., cysteine, homocysteine, mercaptonorvaline, mercaptovaline, mercaptonorleucine, 2-amino-7-mercaptoheptanoic acid, and 2-amino-8-mercaptooctanoic acid.

[0156] A peptide described herein can comprise one or more negatively charged amino acids and / or one or more positively charged amino acids. Positively charged amino acids include, for example, lysine, arginine, histidine, and amino acids that contain additional amine groups. Positively charged amino acids can comprise a heteroaryl substitution such as pyridine, imidazole, pyrazole, or triazole that has one or more ring nitrogen atoms. Negatively charged amino acids include, for example, amino acids that contain an additional carboxylic acid group such as glutamic acid or the like.

[0157] In some embodiments, a cyclic peptide has a net charge of -3 to + 1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. InAttorney Docket No. 01277-0089-00PCT-RYZsome embodiments, a cyclic peptide has a net charge of at most -4. In some embodiments, the cyclic peptide has a net charge of -4. In some embodiments, a cyclic peptide has a net charge of at least +2. In some embodiments, the cyclic peptide has a net charge of +2. In some embodiments, the cyclic peptide has a net charge of +3. The net charge can be determined by aggregating the charge of each of the X1 to X12 amino acids (or each of the amino acid in the peptide). For example, aspartic acid (D) and glutamic acid (E) each has a charge of -1, lysine (K), arginine (R) and histidine (H) each has a charge of +1, and the rest of the canonical amino acids each has a charge of 0.

[0158] In some embodiments, a cyclic peptide has a net charge of -3 to +1. In some embodiments, the cyclic peptide has a net charge of -3. In some embodiments, the cyclic peptide has a net charge of -2. In some embodiments, the cyclic peptide has a net charge of -1. In some embodiments, the cyclic peptide has a net charge of 0. In some embodiments, the cyclic peptide has a net charge of +1. The net charge can be determined by aggregating the charge of each of the amino acids of the cyclic peptide.

[0159] In some embodiments, a cyclic peptide does not contain any S-S bond.

[0160] In some embodiments, a peptide of the present disclosure can be cyclized by forming a group as illustrated in Table 4B.Table 4B. Ring Closing Groups (m and n are independently 0 or an integer from 1 to 6.) -C( ())-< 11 ■-C(=O)-CH2-S- -C(===O)-CH2-S-CH2- -C(=O)-CII2-S-CII2-CH2- -(CH2)m-NH-CO-(CH2)n- -(CH2)m-CO-NH-(CH2)n- -(CH2)m-S-(CH2)n- -(CH2)m-CH=CH-(CH2)n- -(CH2)m-NH-(CH2)n- -(CH2)m-S -CH2-benzene -CH2-S -(CH2)n- -(CH2)m-triazole-(CH2)n- -(CH2)m-succimmide-S-(CH2)n- -C(=O)-CH2-NH-CH2- -C(::: O)-CH2-O-CH2- -C(=O)-CH2-CH2-S- -(CH2)m-S-S-(CH2)n- -(CH2)m-C(=O)-NH-(CH2)n- -(CH2)m-CH2-CH2-(CH2):;-

[0161] In some embodiments, m is 0 and n is 0. In some embodiments, m is 0. In someAttorney Docket No. 01277-0089-00PCT-RYZembodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, n is 0, In some embodiments, n is 1. In some embodiments, n is 2, In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0162] In some embodiments, a peptide of the present disclosure can be cyclized by reacting a first functional group with a second functional group, see Table 4C. In some embodiments, the first functional group is located at the N-terminus. In some embodiments, the first functional group is located at a non-terminal amino acid. In some embodiments, the second functional group is located at the C -terminus. In some embodiments, the second functional group is located at a non-terminal amino acid.Table 4C. Formation of Ring Closing GroupsFirst Functional group (e.g., at N- Second Functional group (or amino acid) (e.g., at C- terminus) terminus or at a non-terminal amino acid) -C(=O)-CH2C1 Cysteine, homocysteine, lysine, homolysine, ornithine, diaminobutric acid, serine, homoserine, threonine, homothreonine-(CH2)„-NH2Aspartic acid, glutamic acid, homoglutamic acid -(CH2)n-CO2H Lysine, homolysine, ornithine, diaminobutric acid, -(CH ) -Br Cysteine, homocysteine-(CH2)n-CH==CH2Allyl-glycine, homoallyl-glycine-(CH2)n-NH2Aspartate-4-semialdehyde, glutamate-5-semialdehyde -(CH2)„-SH Cysteine, homocysteine conjugated with 1,2- or 1,3- or 1,4-bis-(bromomethyl)benzene-(CH2)n-alkyne XaaC is an amino acid with a side chain with azide -(CH2)n-N3Alkynyl-glycine, homoalkynyl-glycine -(CII2)n-maleimide Cysteine, homocysteine

[0163] A peptide described herein can be a peptide mimetic. For example, the peptide can comprise non-peptide bonds and it can comprise one or more unnatural amino acids. Unless stated otherwise, each of the amino acid in a peptide described herein ( except the natural amino acid glycine) can independently be in its D or L form. Both D and L forms are encompassed by the present disclosure.

[0164] In the present disclosure, the term amino acid embraces derivatives of amino acids. The derivatives include, for example, amino acids obtained by modifying a natural amino acid constituting a protein produced by cellular DNA-encoded biological matter. Examples of such non-natural amino acids include hydroxyproline and hydroxy lysine, which are amino acids having a hydroxyl groupAttorney Docket No. 01277-0089-00PCT-RYZintroduced therein, and diaminopropionic acid, which is an amino acid having an amino group introduced therein.

[0165] A peptide described herein can comprise an N-substituted amino acid. In some embodiments, the N-substituted amino acid is a derivative of tryptophan, phenylalanine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, or valine. In some embodiments, the -substitution is an N-alkyl, such as -methyl and N-ethyl. In some embodiments, the N-substitution is N -methyl. In some embodiments, the N-substitution is an N-aryl, such as N-phenyl or N-biphenyl. In some embodiments, the N-substitution is an N-heteroaryl such as N-pyridyl. In some embodiments, tire N-substituted amino acid is at the N -terminus of the peptide, in some embodiments, the N -substituted amino acid is a non-terminal amino acid.

[0166] In some embodiments, peptides described herein comprise one or more amino acids in Tables 5A to 5G.Table 5A. Exemplary Amino Acids at N or C -terminusN - Chloroacetyl - L - alanine Acetyl - L - alanineN - Chloroacetyl - L - phenylalanine Acetyl - L - phenylalanineN - Chloroacetyl - L - phenylalanine Acetyl - L - tyrosineN - Chloroacetyl - L - tyrosine Acetyl - L - tryptophanN - Chloroacetyl - L - tryptophan Acetyl - D - alanineN - Chloroacetyl - D - alanine Acetyl - D - phenylalanineN - Chloroacetyl - D - phenylalanine Acetyl - D - tyrosineN - Chloroacetyl - D - tyrosine Acetyl - D - tryptophanN - Chloroacetyl - D - tryptophan N - 3 - chloromethylbenzoyl - L - tyrosine N - 3 - chloromethyl benzoyl - L - tryptophanTable 5B. Exemplary Ammo Acids That Crosslink With A PeptideNy-(2-chloroacetyl)-a,y-diaminobutylic acidNY-(2-chloroacetyl)-a, Y-diaminopropanoic acidTable 5C. D-amino AcidsD-SerineD-PhenylalanineD-TyrosineD-TryptophanAttorney Docket No. 01277-0089-00PCT-RYZTable 5D. Exemplary N-alkylamino AcidsN-alkyl-GIycineN-alkyl-AlanineN-alkyl-PhenylalanineN-alkyl-TyrosineN-alkyl-SerineN -alkyl -HistidineN -alkyl -Tryptophan

[0167] Exemplary alkyl groups for Table 5D include methyl, ethyl, and propyl groups.Table 5E. Exemplary Peptoid BlocksN-ethyl-GIycineN -n-propyl-Gl yci n eN -n-butyl-GlycineN-n-pentyl-GlycineN-n-hexyl-GIycineN-n-heptyl-GlycineN -n-octy 1-Gly cineN-isopentyl-GlycineN-(2-phenylethyl)-GlycineN-(3 -phenylpropyl) -GlycineN-[2-(p-hydroxyphenyl)ethyl]-GlycineTable 5F. Exemplary Unnatural Amino Acidsp-biphenylalaninep-tri fluoromethylphenylalaninep-azidophenylalaninep-biotinyl-aminophenylalaninee-N -Biotinyl -ly sin ee-N -Acetyl -lysineL-CitrullineL-5 -Hy droxytryptphanL-l,2,3,4,-Tetrahydroisoquinoline-3-carboxylicacidAminoisobutyric acidAttorney Docket No. 01277-0089-00PCT-RYZN-methyl-aminoisobutyric acidN-metltyl-Phenylglycine

[0168] Ammo acids used in the disclosed peptides can be substituted with similar amino acids. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophobicity. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophilicity. In some embodiments, an amino acid can be substituted with another amino acid with similar size. In some embodiments, an amino acid can be substituted with another amino acid with similar charge. In some embodiment, an amino acid can be substituted with another amino acid with a similar functional group. In some embodiments, an amino acid can be substituted with another amino acid with the same functional group.

[0169] In some embodiments, an amino acid described herein can be replaced with a variant thereof. Examples of an amino acid substitution or variant include derivatives having an amine, amide, ester, or carboxyl group as the C -terminus and / or N-terminus thereof. Additional examples of amino acid / peptide variants include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation and fused protein obtained by fusion with another peptide or protein. These variants can be prepared by those skilled in the art in a known manner or a method based thereon. An amino acid variant further encompasses the amino acids that have the same functional groups but with different lengths of the side chain (e.g., LysAc vs. OmAc and cysteine vs. homocysteine). An amino acid variant further encompasses ammo acids with a different aromatic moiety compared to the canonical amino acid (e.g., the indole in tryptophan vs the 7-azaindole in 7-AzaTrp; the phenyl in phenylalanine vs the pyridine in 4Py ). An amino acid variant further encompasses amino acids with optional substituents, i.e., optionally substituted amino acid. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, amino, amide, nitro, ureido, Cj-Ce alkyl, Cj-Ce alkoxy, Cg-Cioaryl, Cj-Ce cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, oxo, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), Si*. -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O) ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRaAttorney Docket No. 01277-0089-00PCT-RYZ(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2),and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (==N-H), oximo (==N-0H), hydrazine (-N-NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0R3, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0R3, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa(where t is 1 or 2), -Rb-S(O)fRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(0)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo ( S). cyano (-CN), nitro (-N02), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-0C(0)-R3, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0R3, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is I or 2), -Rb-S(0)t0R3(where t is 1 or 2) and -Rb-S(0)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0170] In some embodiments, a variant of an amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(Ci-C3alkyl), -N(Ci-C3alkyl)2, oxo, -OH, -CO2H, -CO2-Ci-C3alkyl, -C(==O)NH2, -C(===O)NH(Ci-C3alkyl), -C(==O)N(Ci-C3alkyl)2, -S(===O)2NH2, -S(===O)2NH(C;- Csalkyl), -S(=O)2N(Ci-C3alkyl)2, Ci-Cs, alkyl, Ci-Cs heteroalkyl, Ci-Ct, alkoxy, Cs-Cioaryl, Cs-Cs cycloalkyl, 6-10 membered heterocycloalkyl, and 6-10 membered heteroaryl. In some embodiments, the variant is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(Ci -Chalky 1), -N(Ci-C3alkyl)2, oxo, -OH, -CO2H, -CO2-Ci-C3alkyl, -C(=O)NH2, -C(=O)NH(Ci-C3alkyl), - C(=O)N(Ci-C3alkyl)2, and Ci-Ce alkyl. In some embodiments, the variant is selected from ammo acids having one or t 'o substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(Ci-C3alkyl), - (Ci-C3alkyl)2, and Ci-C* alkyl. In some embodiments, the variant is selected from amino acids having one or tw o substituents based on the amino acid, and wherein the substituents are independently selected from Ci-Cg alkyl.

[0171] In some embodiments, a variant of an amino acid is selected from amino acids that have the similar hydrophilicity or hydrophobicity compared to the amino acid. Thus, in some embodiments, a positively charged amino acid can be a variant of another positively charged amino acid. In some embodiments, a negatively charged amino acid can be a variant of another negatively charged amino acid. In some embodiments, a zwitterionic amino acid can be a variant of another zw itterionic aminoAttorney Docket No. 01277-0089-00PCT-RYZacid.

[0172] In some embodiments, a hydrophilic amino acid has an electrically charged side chain. In some embodiments, a hydrophilic amino acid has a positive charge. In some embodiments, a hydrophilic amino acid has a negative charge. In some embodiments, a hydrophilic amino acid is zwitterionic (e.g., KCOpipzaa). In some embodiments, a hydrophilic amino acid comprises a -OH, COOH, -NH- or NH2moiety. In some embodiments, a hydrophilic amino acid comprises -OH, -C(O)OH, -NHC(=NH)NH2, -NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3In some embodiments, a hydrophilic amino acid comprises a side chain of Ci-Cehydroxy lkyl, Ci-Cgaminoalkyl, -Co-s alkylene-NH-C(:::NH)-NH2, -C0.6alkylene-CO-NH2, -C0.6alkylene-COOH, or -NH-CO-C1 6alkyl.

[0173] In some embodiments, a hydrophobic amino acid is not charged. In some embodiments, a hydrophobic amino acid contains at least 2 contiguous carbon atoms. In some embodiments, a hydrophobic amino acid comprises at least 3 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 4 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 5 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises an ethylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a propylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a butylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises phenyl moiety. In some embodiments, a hydrophobic amino acid comprises a heteroaryl moiety. In some embodiments, a hydrophobic amino acid is Trp, Tyr, Phe, or derivatives thereof.

[0174] In some embodiments, a variant of an amino acid is selected from amino acids that have the same functional group as the amino acid, and wherein the variant has a different length of a side chain compared to the amino acid. In some embodiments, a variant of an amino acid is selected from amino acids that have the same charge compared to the amino acid. In some embodiments, a variant of an amino acid is selected from amino acids that have the same polarity compared to the amino acid. In some embodiments, an amino acid comprising an aromatic group can be a variant of another amino acid having an aromatic group. In some embodiments, an amino acid comprising a phenyl can be a variant of another amino acid having a phenyl. In some embodiments, an amino acid comprising a heteroaryl can be a variant of another amino acid having a heteroaryl. Amino acids having an aromatic group include, but are not limited to, F, W, F4G, 4Py,3Py, F4COO, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F4C, F4OMe, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, F4amCOpipzaa, F4u, F4CONdMe, F4ms, F34dOMe, F3C, F3CONdMe, 5Inda, F3aa, 3Py6MHae, 3Py6OMe, MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeW7N, MeF3C4Me, MeF3Me4C, Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F4IPyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4Pip, PhNva, PhNle, Yph, Ybn, F4tb, F4OPr, Yae, Me3Py, W5N and MeWlMe.Attorney Docket No. 01277-0089-00PCT-RYZ

[0175] In some embodiments, an amino acid comprising a cycloalkyl group can be a variant of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a vanant of another amino acid having a heterocycloalkyl group,

[0176] In some embodiments, a variant of an amino acid is selected from amino acids that have similar polarity and / or charge with the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be a variant of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Qglucamine),

[0177] In some embodiments, a variant of an amino acid has the same number of hydrogen donor as the amino acid. In some embodiments, a variant of an amino acid has the same number of hy drogen acceptor as the amino acid.

[0178] In some embodiments, the variant has a molecular weight that does not vary’ for more than 14, 28, 30, 45 or 60 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that does not vary for more than 14 g / mol compared to the amino acid. In some embodiments, the variant has a molecular weight that does not vary for more than 50 g / mol compared to the ammo acid. In some embodiments, the variant has a molecular weight that does not vary’ for more than 28 g / mol compared to the amino acid.

[0179] An amino acid variant further encompasses amino acids wherein a functional group is substituted with another functional group having similar properties, e.g., a cysteine can be substituted with a homocysteine. In some embodiments, an aryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, an amino functional group can be substituted with an NH(alkyl) group.

[0180] As used herein, the expression “conservative amino acid substitution” refers to a substitution of functionally equivalent or similar amino acids. A conservative amino acid substitution in a peptide brings about a static change to the amino acid sequence of the peptide. For example, one or two or more amino acids having similar polarity act functionally equivalent to each other and bring about a static change in the amino acid sequence of the peptide. In general, a substitution within a certain group may be considered conservative regarding structure and function. However, as is clear to a person having ordinary skill in the art, the role played by a defined amino acid residue may be determined by its implication in the three-dimensional structure of the molecule containing the amino acid. For example, a cysteine residue in an oxidized-type (disulfide) form may have a lower polarity than that of a reduced-type (thiol) form. The long aliphatic part of the arginine side chain may constitute structurally and functionally important features. Furthermore, the side chain (tryptophan, tyrosine, phenylalanine) including an aromatic ring may contribute to ion-aromatic interaction or cation-pi interaction. In such a case, even if the amino acids having these side chains are substituted for amino acids belonging to the acidic or non-polar groups, they may be structurally and functionally conservative. There is a possibility that residues such as proline, glycine, cysteine (disulfide form)Attorney Docket No. 01277-0089-00PCT-RYZhave a direct effect on the three-dimensional structure of the main chain and often may not be substituted without structural distortion.

[0181] Conservative amino acid substitution, as shown below, includes specific substitution based on the similarity of side chains (for example, substitutions are described in Lehninger, Biochemistry, Revised 2nd Edition, published in 1975, pp. 73 to 75: L. Lehninger, Biochemistry, 2nd edition, pp. 73 to 75, Worth Publisher, New York (1975)), incorporated herein by reference, and typical substitution.

[0182] Hydrophobic amino acids include amino acids that exhibit hydrophobicity, including alanine (also referred to as “Ala” or simply “A”), glycine (also referred to as “Gly” or simply “G”), valine (also referred to as “Vai” or simply “V”), leucine (also referred to as “Leu” or simply 'I. '), isoleucine (also referred to as “He” or simply “I”), proline (also referred to as “Pro” or simply “P ”), phenylalanine (also referred to as “Phe” or simply “F”), tryptophan (also referred to as Trp” or simply “W”), tyrosine (also referred to as “Tyr” or simply W”), and methionine (also referred to as “Met” or simply “M”).

[0183] Exemplary hydrophobic amino acids may be further divided into the following groups:• Aliphatic amino acids: Amino acids having a fatty acid or hydrogen in the side chain, including e.g., Ala, Gly, Vai, He, and Leu.• Aliphatic / branched-chain amino acids: Amino acids having a branched fatty acid in the side chain, including e.g., Vai, He, and Leu.• Aromatic amino acids: Amino acids having an aromatic ring in the side chain, including e.g., Trp, Tyr, and Phe.

[0184] In some embodiments, a hydrophobic amino acid has a Cl -C8 alkyl, cycloalkyl, or heterocycloalkyl, -wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently, optionally substituted. In some embodiments, a hydrophobic amino acid has a C1-C8 alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each unsubstituted. In some embodiments, a hydrophobic amino acid has a C3-C6 unsubstituted alkyl. In certain embodiments, a hydrophobic amino acid is I, Eva, all, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg.

[0185] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including e.g., serine (also referred to as “Ser” or simply “S”), threonine (also referred to as “Thr” or simply “T”), cysteine (also referred to as “Cys” or simply “C”), asparagine (also referred to as “Asn” or simply “N”), glutamine (also referred to as “Gin” or simply “Q”), aspartic acid (also referred to as “Asp” or simply “D”), glutamic acid (also referred to as “Glu” or simply “E”), Elysine (also referred to as “Lys” or simply “K”), arginine (also referred to as “Arg” or simply “R”), and histidine (also referred to as “His” or “H”).

[0186] Exemplary' hydrophilic amino acids may be further divided into the following groups:® Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu.Attorney Docket No. 01277-0089-00PCT-RYZ• Basic amino acids: Amino acids whose side chains exhibit basicity, including Lys, Arg, and His,• Neutral amino acids: Amino acids whose side chains exhibit neutrality, including Ser, Thr, Asn, Gin, and Cys.

[0187] Exemplary hydrophilic amino acids include, for example, D, Q, A, E, S, N, T, C, H, or a vanant thereof (including D-amino acid such as da and variations such as KCOpipzetOH, Cit, COmeglumine, KCOpipzaa, A4paa, Hgl, F4COO, KCOpip4COO, KAc, Hgn, Har, DapCOpipzaa, Acpr, Cba, NleCOO, NleOH, Atb, Nva, Nle, DapAc, Abu, Nmm, Ndm, Ncit, Cit or the like). In some aspect, hydrophilic amino acid is optionally N-methylated such as MeD.

[0188] In some embodiments, a peptide described herein comprises an amino acid that affects the direction of the main chain, e.g., Gly and Pro. In some embodiments, a peptide described herein comprises a sulfur-containing amino acid, e.g., Cys and Met. In some embodiments, a peptide described herein comprises an amino acid that comprises an aromatic ring, which can be optionally substituted. Ammo acids comprising an aromatic ring include, e.g., F (Phe; phenylalanine), Y (Tyr: tyrosine), W (Trp; tryptophan).

[0189] In some embodiments, W or a variant thereof can be W, an amino acid having a heteroatom in the indole ring of W in the side chain, an amino acid in which the hydrogen of NH in the indole ring of W is substituted, or an amino acids having a substituent in the benzene ring of W, or the like.

[0190] In some embodiments, F or a variant thereof can be F (phenylalanine), an amino acid comprising a phenyl, 6 membered heteroaryl (such as pyridine, pyrimidine, pyrazine), indazolyl, or naphthalyl in its side chain, wherein said phenyl, heteroaryl, indazolyl or naphthaly l is optionally substituted. In some embodiments, F or a variant thereof can be F (phenylalanine), an ammo acid comprising a phenyl, naphthalyl, 6 membered heteroaryl, or bicyclic heteroaryl in its side chain, wherein said phenyl, heteroaryl, or naphthalyl is optionally substituted. In some embodiments, F or a variant thereof can be F (phenylalanine), an amino acid comprising a phenyl, pyridinyl, indazolyl, or naphthalyl in its side chain, wherein said phenyl, pyridinyl, indazolyl or naphthalyl is optionally substituted with one or more substituents each independently selected from halogen, -Cl-3alkyl, -OH, -NH2, -CN, -C(=O)OH, -C(=O)NH2, -NHC(=O)CH3, -C1-3alkylene-C(=O)OH, -C1-3alkylene-C(=O)NH2, -O-C1-3alkylene-C(=O)OH, -O-C1-3alkylene-C(=O)NH2, -C1-3alkylene-C(=O)-5- to 6-membered heterocycloalkylene-C1-3alkylene-C(=O)OH, -O-C1-3alkylene-C(=O)-5- to 6-membered heterocycloalkylene-C1-3alkylene-C(=O)OH, -Cl-3alkylene-NFIC(=O)- 5- to 6-membered heterocycloalkylene-Cl-3alkylene-C(=O)OH, -O-C1-3alkylene-NHC(=O)-5- to 6-membered heterocycloalkylene-C1-3alkylene-C(=O)OH, and -NH-Cl-3alkylene-C(=O)OH, -NHC(=O)NH2, -C1-3alkylene-C(NH2)-COOH, -NH-CO-CH3, -NH-C1-3alkylene-NH2, -C(=O)-N(CH2)2, -S(=O)2-CH3, -C1-3alkylene-NH-C(=O)-5- to 6-membered heterocycloalkylene-C1-3alkylene-C(=O)OH, and -O-C1-3alkylene-NH-C(=O)-5- to 6-membered heterocycloalkylene-C1-3alkylene-C(=O)OH, -O-phenyl, -O-C1-3alkylene-phenyl, pyridinyl, imidazolyl, pyrazolyl, N-C1-3alkylene pyrazolyl, N-C1-3alkylene(-O-Attorney Docket No. 01277-0089-00PCT-RYZC1-3alkyl) pyrazolyl, pyranyl, tetrahydropyranyl, piperidinyl, N-C1-3alkylene-C(=O)-piperidinyl; or the like. In some aspect, F or a variant thereof is optionally N-methylated.

[0191] In some embodiments, F or a variant thereof can be F (phenylalanine), an amino acid wherein (i) the phenyl ring of F is substituted with 1 or 2 substituents each independently selected from -OH, -CN, -C1.3 alkyl, such as -CH3; (ii) a 6-membered heteroaryl ring optionally substituted by 1 or 2 substituents each independently selected from -OH, -CN, - C13 alkyl, such as -CH3; or (iii-1) having a heteroatom in the phenyl ring of F in the side chain; (iii-2) a derivative amino acid of F in which a 6-membered heteroaryl ring in the side chain is substituted; or the like. In some aspect, F or a variant thereof is optionally N-methylated.

[0192] In some embodiments, Y or a variant thereof can be Y, an amino acid having a hydroxyphenyl ring, wherein the hydrogen atom in hydroxyphenyl of Y or of the variant is optionally substituted. In some embodiments, Y or a variant thereof can be Y, an amino acid having a hydroxyphenyl ring, wherein the hydrogen atom in hydroxyphenyl of Y or of the variant is optionally- substituted with one or more substituents selected from -Cl-3alkyl, -Cl-3alkylene-C(=O)OH, halogen, -OH, -C(=O)OH, -O-CH3, -Ci.3alkylene-C(=O)- 5- to 6-membered heterocycloalkylene-Ci 3alkylene-C(=O)OH, and -Ci-3alkylene-NHC(=O)- 5- to 6-membered heterocycloalkylene-Ci.3alkylene-C(=O)OH. In some embodiments, a variant of W or a variant thereof can be W, WIMe, or W7N or the like. In some embodiments, W or a variant thereof is optionally N-methylated (e.g., MeW1Me or MeW7N).

[0193] In certain embodiments, F or Y or a variants thereof is Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, Almor, F4amC0pipzaa, F4OMe, F4u, F4CONdMe, F4ms, F34dOMe, F3C, F3CONdMe, 5Inda, F3aa, 3Py6Nhae, 3Py6OMe, F4amCOpipzaa, Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, or F4oPr.

[0194] In some embodiments, a monocyclic aromatic amino acid can be an amino acid having a phenyl or monocyclic heteroaryl, each of which optionally substituted. In some embodiments, a monocyclic aromatic amino acid can be an amino acid having a phenyl or pyridinyl optionally substituted with one or more substituents each independently selected from halogen, -Cl-3alkyl, and trifluoromethyl. In some embodiment, a bicyclic aromatic amino acid can be an amino acid having a naphthalyl or bicyclic heteroaryl, each of which optionally substituted. In some embodiment, a bicyclic aromatic amino acid can be an amino acid having a naphthalyl, quinolyl, or indazolyl optionally substituted with one or more substituents each independently selected from H or Cl-3alkyl. In some embodiments, bicyclic aromatic acid can be W (tryptophan), or a variant thereof, or N-methylated thereof. In certain embodiments, a monocyclic aromatic amino acid is MeF3C3Me, MeF34dOMe, MeF4T,or MeF3Me4C. In certain embodiments, a bicyclic aromatic amino acid isAttorney Docket No. 01277-0089-00PCT-RYZMeNal2, MeNal27N, MeF34diox, MeWIMe, or MeW7N.

[0195] In some embodiments, an amino acid described herein is N-alkylated.

[0196] In some embodiments, an amino acid described herein is not N-alkylated (e.g., an amino acid with -H on the alpha-amino group).

[0197] Examples of the amino acids include natural protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art as characteristics of an amino acid. Examples of the unnatural amino acids include, but not limited to, a,a-disubstituted amino acids (such as a-methylalanine), N-alkyl-a-amino acids, D-amino acids, P-amino acids, and a-hydroxy acids, each having a backbone structure different from that of natural amino acids; amino acids (such as norleucine and homohistidine) having a side-chain structure different from that of natural amino acids; amino acids (such as “homo” amino acids, homophenylalanine, and homohistidine) having extra methylene in the side chain thereof; and amino acids (such as cysteic acid) obtained by substituting a carboxylic acid functional amino group in the side chain thereof by a sulfonic acid group.

[0198] The peptides described herein can comprise one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to an amino acid residue on a polypeptide subjected to modification after expression (ex. phosphorylated tyrosine, acetylated lysine, or famesylated cysteine), (2) amino acids that cannot be used in expression on a ribosome but occur naturally, and (3) artificial amino acids that do not occur naturally (unnatural ammo acids). Non-limiting examples of unnatural amino acids include: p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p-methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4- propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, Boronophenylalanine, O-propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L- phenylalanine, isopropyl-L-phenylalanine, and azido-lysine (AzK). In some embodiments, the unnatural amino acid is an unnatural analogue of a tyrosine amino acid; an unnatural anal ogue of a glutamine amino acid; an unnatural analogue of a phenylalanine amino acid; an unnatural analogue of an alanine amino acid; an unnatural analogue of a serine amino acid; an unnatural analogue of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynyl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid; or a combination thereof. In some embodiments, the unnatural amino acid is an amino acid with a photoactivatable cross-linker; a spin- labeled amino acid; a fluorescent amino acid; a metal binding amino acid; a metal -containing amino acid; a photocaged and / or photoisomerizable amino acid; a biotin or biotin-analogue containing amino acid; a keto containing amino acid; an amino acid comprising polyethylene glycol or polyether; aAttorney Docket No. 01277-0089-00PCT-RYZheavy atom substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid with an elongated side chain; an amino acid containing a toxic group; a sugar substituted amino acid; a carbon-linked sugar-containing amino acid; a redox-active amino acid; an a-hydroxy containing acid; an amino thio acid; an a, a-disubstituted amino acid; a P-amino acid; a cyclic amino acid other than proline or histidine, or an aromatic amino acid other than phenylalanine, tyrosine or tryptophan.

[0199] Unnatural amino acids include, for example, N-alkyl amino acids in which a natural amino acid described above is N-alkylated, e.g., those modified with lower alkyl groups (for example, of Cl to C5, Cl to C3, and Cl) in which the nitrogen forming a peptide bond is branched or not branched. Exemplary N-alkyl amino acids include, e.g., N -ethyl amino acid, N-butyl amino acid, and N-methyl amino acid. Also included are amino acids to which a functional group is further added to the side chain of a natural amino acid or substituted for another functional group (for example, an amino acid having a substitution or an addition in a part such as an arylene group, an alkylene group, or the like of the side chain; an amino acid wherein the arylene group or the alkyl group of the side chain has an increased C -number; an amino acid having a substitution in the aromatic ring of the side chain; a heterocyclic or condensed cyclic amino acid; or the like). Exemplary N-alkyl amino acids further include, e.g., N-alkyllysine and N-methyllysine.

[0200] In a non-limiting manner, unnatural amino acids include, but are not limited to N-methyl amino acids, F4G, 4Py, 3Py, Cit, KCOpipzaa, Eva, Ahp, F4COO, KCOpip4COO, Aib, Hpr, Sbu, MeDapCOpipzaa, Scbm, Scpe, HseBu, A4paa, Spent, Hgl, Hsecpe, Hgn, DapCOpipzaa, MeD, CmG, Medd, HseEt, HseiPr, CrmG, CeG, CrpG, MeHgl, MeCit, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F4C, F4OMe, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, Almor, F4amCOpipzaa, Chg, Tbg, Gcpr, Gcpe, Acpr, Cba, Gthp, NleCOO, NleOH, Atb, Nva, Nle, DapAc, Abu, Ncit, dMeS, TdMe, Cbg, NvaOMe, NleOMe, AhpOMe, F4u, F4CONdMe, F4ms, F34dOMe, F3C, F3CONdMe, 5Inda, F3aa, 3Py6NHae, 3Py6OMe, MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeW7N, MeF3C4Me, MeF3Me4C, Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4Pip, PhNva, PhNle, Yph, Ybn, F4tb, F4OPr, S3REt, Yae, datb, Me3Py, W5N, MeA4paa, Mel, MeA, MeG, MeV, MeT, all, TMe, MeQ, MeTMe, MeK, MeKAc, Har, KAc, dd, EtG, K(biotin), MeeG, CmpG, Nmm, Ndm, SMe, HseMe, SiPr, SPr, MeWIMe, MeQdMe, MeSMe, MeHseMe, MeKCOpipzaa, KCOpipzetOH, KCOmeglumine, MeK(de), MeK(H), MeK(df), MeK(datb), and the like. Note that D-amino acids such as da may be classified as D-amino acids, but they may also be classified according to the properties of their side chains, and N-methy l amino acids may be classified as N-alkyl amino acids and may also be classified according to the property of the side chain.

[0201] In some embodiments, the unnatural amino acids incorporated into the peptides include oneAttorney Docket No. 01277-0089-00PCT-RYZor more of: 1) a ketone functional group (as found in para or meta acetyl-phenylalanine) that can be specifically reacted with hydrazines, hydroxylamines and their derivatives (Addition of the keto functional group to the genetic code of Escherichia coli. Wang L, Zhang Z, Brock A, Schultz P G Proc Natl Acad Sci USA. 2003 Jan. 7; 100( 1):56-61; Bioorg Med Chem Let. 2006 Oct. 15;16(20): 5356-9. Genetic introduction of a dike tone -containing amino acid into proteins. Zeng H, Xie J, Schultz P G), 2) azides (as found in p-azido-phenylalanine) that can be reacted with alkynes via copper catalyzed “click chemistry’” or strain promoted (3+2) cycloadditions to form the corresponding triazoles (Addition of p-azido-L-phenylalanine to the genetic code of Escherichia coli. Chin J W, Santoro S W, Martin A B, King D S, Wang L, Schultz P G. J Am Chem Soc. 2002 Aug. 7;124(31 ): 9026-7; Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. Deiters A, Cropp T A, Mukherji M, Chm J W, Anderson J C. Schultz P G. J Am Chem Soc. 2003 Oct. 1; 125(39): 11782-3), or azides that can be reacted with aryl phosphines, via a Staudinger ligation (Selective Staudinger modification of proteins containing p -azidophenylalanine. Tsao M L, Tian F, Schultz P G. Chembiochem. 2005 December; 6(12):2147-9), to form the corresponding amides, 3) alkynes that can be reacted with azides to form the corresponding triazole (In vivo incorporation of an alkyne into proteins in Escherichia coli. Deiters A, Schultz P G. Bioorg Med Chem Let. 2005 Mar. 1; 15(5): 1521-4), and 4) boronic acids (boronates) than can be specifically reacted with compounds containing more than one appropriately spaced hydroxyl group or undergo palladium mediated coupling with halogenated compounds (Angew Chem Int Ed Engl. 2008;47(43): 8220-3. A genetically encoded boronate-containing amino acid., Brustad E, Bushey M L, Lee J W, Groff D, Liu W, Schultz P G).

[0202] The peptide of the present disclosure embraces various derivatives thereof. Examples of the derivatives include derivatives having an amide, ester, or carboxyl group as the C-terminus and / or N-terminus thereof. Additional examples of the derivatives of the peptide include those obtained by modification such as phosphorylation, methylation, acetylation, adenylylation, ADP-ribosylation, or glycosylation and fused protein obtained by fusion with another peptide or protein. These derivatives can be prepared by those skilled in the art in a known manner or a method based thereon.

[0203] In some embodiments, the peptide described herein comprises a basic ammo acid. Examples of the basic amino acid include arginine, lysine, citrulline, ornithine, creatine, histidine, diamino butanoic acid, and diaminopropionic acid.

[0204] In some embodiments, provided herein is a peptide having 90% or more sequence identity’ to any? of sequences disclosed herein. In some embodiments, the sequence identity is at least 95% or 99%.

[0205] The conjugates of the present disclosure embrace salts thereof. Physiologically acceptable base or acid are used to create salt forms of the radiopharmaceutical conjugates. Examples include addition salts with an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, or phosphoric acid), addition salts with an organic acid (such as p -toluene sulfonic acid.Attorney Docket No. 01277-0089-00PCT-RYZmethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, or acetic acid), inorganic bases (such as ammonium hydroxide, alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate), and an amino acid.

[0206] In certain embodiments, the peptides and conjugates described herein comprises one or more unnatural amino acids that are not any one of the 20 canonical amino acids found in proteins. Representative unnatural amino acids that can be incorporated into the peptides and conjugates described herein are described herein.Linker

[0207] A conjugate described herein can comprise one or more linkers. In some embodiments, the linker covalently attaches the peptide with the metal chelator. In some embodiments, the peptide attaches directly to the metal chelator without a linker. In some embodiments, the present disclosure describes linkers that function as a spacer.

[0208] A conjugate described herein can comprise a linker. The linker can comprise a number of intervening atoms (on a linear chain, excluding pendant groups or substituents) between the metal chelator or covalently bound radionuclide and the binding peptide described herein, thereby creating a distance between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 10-100 intervening atoms between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 2-60 intervening atoms between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 intervening atoms between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 3 to 30 intervening atoms between tire metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 5 to 25 intervening atoms between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 6 to 18 intervening atoms between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, a linker comprises 10 to 20 intervening atoms between the metal chelator or covalently bound radionuclide and the binding peptide. In some embodiments, the linker comprises 3 to 10 intervening non-hydrogen, organic atoms between the metal chelator and the peptide.

[0209] The intervening atoms can comprise 1 or more carbons, and optionally one or more heteroatoms such as O and N, In some embodiments, the intervening atoms comprise 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 carbons. In some embodiments, the intervening atoms comprise 0, 1, 2, 3, 4, 5, or 6 nitrogen. In some embodiments, the intervening atoms comprise 0, 1, 2, 3, 4, 5, 6, 7 or 8 oxygen. In some embodiments, the intervening atoms comprise 1 to 6 nitrogen and 0 to 4 oxygen.

[0210] A linker can comprise one or more amino acid residues. In some embodiments, the linkerAttorney Docket No. 01277-0089-00PCT-RYZcomprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the linker comprises 1 to 5 amino acid residues. For example, the linker can comprise one or more lysine (K) residues such as K, KK, or KICK sequences. In some embodiments, the linker comprises a lysine or a derivative thereof. In some embodiments, the linker comprises a lysine. In some embodiments, one or more amino acids of the linker are unnatural amino acids. In some embodiments, the linker comprises a lysine residue, an alanine residue, or both. In certain embodiments, the linker comprises one or more amino acids chosen from a lysine residue, an alanine residue, or a phenylalanine residue. In some embodiments, the linker comprises a lysine residue. In some embodiments, the linker comprises an alanine residue. In some embodiments, the linker comprises a lysine residue, an alanine residue, a glycine residue, a D-phenylalanine residue, a histidine residue, a dAtb residue, or a D-glutamate residue. In some embodiments, the linker comprises 2 amino acids selected from the group consisting of lysine, alanine, glycine, D-phenylalanine, histidine, dAtb, and D-glutamate.

[0211] A herein-described linker can attach to the N -terminus of the peptide, the C -terminus of the peptide, or a non-terminal amino acid of the peptide, or it can attach to the peptide through a combination of the above. In some embodiments, the linker is attached to the peptide via its N-terminus. In some embodiments, the linker is attached to the peptide via a cysteine residue at the C- tenninus. In some embodiments, the linker is attached to the peptide via a cysteine residue at the N- terminus. In some embodiments, the linker is attached to the peptide via its C-terminus. In some embodiments, the linker is attached to the peptide via a non-terminal amino acid. The linker can be bonded to the peptide, the payload molecule, or both, for example, through a chemically reactive group. Exemplary chemically reactive groups include, but are not limited to, a free amino, imino, hydroxyl, thiol or carboxyl group (e.g., to the M- or C-terminus, to the epsilon amino group of one or more lysine residues, the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cy steinyl residues). The site to which the linker is bound to the peptide can be a natural or unnatural amino acid of the peptide and / or it can be introduced into the peptide, e.g., by DNA recombinant technology (e.g., by introducing a cysteine or protease cleavage site in the amino acid sequence) or by protein biochemistry (e.g., reduction, pH adjustment or proteolysis). Exemplary methods for attaching the linker includes carbodiimide reaction, reactions using bifunctional agents such as dialdehydes or imidoesters, Schiff base reaction, Suzuki-Miyaura cross-coupling reactions, Isothiocyanates as coupling agents, and click chemistry.

[0212] The linker can have a prescribed length thereby linking the metal chelator and the peptide while allowing an appropriate distance therebetween. In some embodiments, the linker has 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, tire linker has 1 to 10 atoms in length. In some embodiments, the linker comprises 3 to 10 intervening non -hydrogen, organic atoms between the metal chelator and the peptide.

[0213] The linker can comprise flexible and / or rigid regions. Exemplary flexible linker regionsAttorney Docket No. 01277-0089-00PCT-RYZinclude those comprising Gly and Ser residues ( ’GS' linker), glycine residues, alkylene chain, PEG chain, etc. Exemplary rigid linker regions include those comprising alpha helix-forming sequences (e.g., EAAAK (SEQ ID NO: 400)), proline-rich sequences, and regions rich in double and / or triple bonds.

[0214] In some embodiments, a linker may be further added to the cyclic peptide. Examples of the linker include an amino acid linker (peptide linker), a chemical linker, a fatty acid linker, a nucleic acid linker, a sugar chain linker, or the like, or it may be a complex, for example, a chemical linker, a peptide linker, or the like. Examples of the chemical linker include a PEG (polyethylene glycol) linker. For example, the PEG linker may comprise between 1 to 24 ethylene glycol units.Furthermore, the linker may be a fatty acid linker containing a divalent chemical moiety derived from a fatty acid. The linker includes at least one amino acid, and, for example, a glycine-rich peptide such as a peptide having a sequence [Gly-Gly-Gly-Gly-Ser] n (in the formula, n is 1, 2, 3, 4, 5, or 6) (SEQ ID NO: 401) such as that according to US Patent No. 7,271,149, incorporated by reference herein, or a serine-rich peptide linker according to US Patent No. 5,525,491, incorporated by reference herein, may be used. In a non-limiting manner, there are some cases where a physical property (for example, solubility) of the peptide may be changed by the addition of a linker. In one aspect, the amino acid linker includes an amino acid sequence according to any one of SEQ ID NOs: 1 to 72.

[0215] The linker may be added at any position. In some embodiments, the linker may be bound to Cys positioned on the C-terminal side or may be bound to an amino acid comprised in the cyclic peptide. In some embodiments, the linker is bound to Cys or variant thereof positioned on the C- terminal side. In some embodiments, the linker is added to the -COOH on the Cys or variant residue. It is possible to add one to several amino acids to the C -terminus of such Cys or cysteine variant, such as MeC, and then the linker is added to its terminus; for example, Gly is added to the C -terminus of Cys or cysteine variant, such as MeC, within the cyclic structure peptide, then the -COOH of the Gly is bound to linker, such as a PEG linker or an amino acid linker. In some embodiments, the linker is added to the side chain of an amino acid within the cyclic peptide. In some embodiments, the linker is added to the side chain of a ly sine within the cyclic peptide. In some embodiments, the linker is added to the side chain of XI, X4, X5, X8, or X12 of Formula I.

[0216] The linker can be cleavable, e.g., under physiological conditions, e.g., under intracellular conditions, such that cleavage of the linker releases the payload molecule in the intracellular environment. The linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include cathepsins B and D and plasmin. In other embodiments, the linker is not cleavable. In some embodiments, the linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. For example, the pH-sensitive linker can be hydrolyzable under acidic conditions. For example, a linker can be an acid-labile linker that is hydrolyzable in the lysosome (e.g., a hydrazone,Attorney Docket No. 01277-0089-00PCT-RYZsemicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like). Such linkers can be relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In some embodiments, the hydrolyzable linker is a thioether linker.

[0217] In some embodiments, the linker comprises an amino acid sequence, such as a combination of amino acid sequence and a flexible and / or rigid region.

[0218] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker comprises substituted or unsubstituted C1-C30 alkylene. In some embodiments, the linker comprises substituted or un substituted C1-C30 heteroalkylene. In some embodiments, the linker comprises polyethylene glycol such as (-CH2-CH2-O-)n.

[0219] In some embodiments, the linker has a structure ofJ Formula (II- 1)wherein each L is independently -O-, -NRL-, -N(RL?+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(==O)NRL-, -NRLC(=S)NRL-, -CRL== -, -N==CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted ary l, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, substituted or unsubstituted C1-C30 heteroalkylene, -(C1-C30 alkylene)-O-, -0-(Ci-C3o alkylene)-, -(C1-C30 alkylene)-NRL-, -NRL-(C1-C30 alkylene)-, -(C1-C30 alkylene)-N(RL)2+-, -N(RL)2+-(C1-C30 alkylene)-, or a click chemistry residue; and each RLis independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted Cs-Cs cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or un substituted heteroaryl; andn is 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).[Formula structure - see image]In some embodiments, the linker has a structure of Formula (II-2), n = 1-20, wherein each L is independently -O-, -NRL-, -N(RLX+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C=C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -N-NRLC(=O)O-, -NRLC(==0)NRL-, -NRLS(==O)2-, -S(==O)2NRL-, -C(===O)NRLS(==O)2-, or -Attorney Docket No. 01277-0089-00PCT-RYZ-S(=O)2NRLC(=O)-.

[0220] In some embodiments, the linker of Formula (II- 1) has a structure of Formula (II- la),L¹ L² L³ L⁴ L⁵ Formula (II-1a) wherein each of L1and L3is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, - S(::::O)—, -S( O)2-, -CH=CH-, =CH-, -C≡C-, -C(===O)-, -C(=O)O-, -OC(=O)-, -OC(===O)O-, - C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=0)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-; and L2is absent, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

[0221] In some embodiments, the linker comprises a structure of Formula (II- lb),L¹ L² L³ L⁴ L⁵ Formula (II-1b)Formula (II- lb)whereineach of L1and L5is independently -O-, -NRL-, -N(RL)2-, -OP(::O)(ORL)O-, -S-, - S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C=C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NRL-, -NRLC(=0)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted 5-6 membered cycloalkyl, or substituted or unsubstituted 5-6 membered heterocycloalkyl; and L2, L3and L4are each independently absent, substituted or unsubstituted 5-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalky, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

[0222] In some embodiments, L‘ is -NH-.

[0223] In some embodiments, L2is absent. In some embodiments, L2is substituted or unsubstituted C1-C30 alkylene, or substituted or un substituted C1-C30 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L2is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C1-C15 alkylene, or substituted or unsubstituted C1-C15 heteroalkylene. In some embodiments, L2is optionally substituted. In some embodiments, L2is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL. In some embodiments, L2is C1-C30 heteroalkylene that is optionally substituted with one or more substituents selected from -OH, -SH, oxo, amino, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl.Attorney Docket No. 01277-0089-00PCT-RYZarid Ci -C& aminoalkyl. In some embodiments, L2 is optionally substituted with Ci-Cs alkyl which is further optionally substituted with one or more substituents chosen from -OH, -SH, oxo, amino, Cs-Cio aryl, 6- to 10- membered heteroaryl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NR1C(=O)ORL.

[0224] In some embodiments, L3is -NH-. In some embodiments, L’ is absent.

[0225] In some embodiments, L4is absent. In some embodiments, L4is substituted or unsubstituted 5-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalky, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

[0226] In some embodiments, L5is -NH-. In some embodiments, L1is absent.

[0227] In some embodiments for Formula (II- lb), L1is -O-, -N(methyl)-, -NH- or -C(=O)-; L5is -O-, -N(methyl)-, -NH- or -C(=O)-; L2, 1 and I? are each independently absent, substituted or unsubstituted 5-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalky, substituted or unsubstituted C1-C12 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene, wherein L1is connected to the payload molecule and 12 is connected to the GPC3 binding peptide.

[0228] In some embodiments for Formula (II- lb), L2is unsubstituted C1-C12 alkylene, and I? and L4are absent.

[0229] In some embodiments, the linker comprises substituted or unsubstituted C1-C30 alkylene, Cj-C12 alkylene, Ci-Cs alkylene, Ci-Cg alkylene, or C2-C6 alkylene. In some embodiments, the linker comprises C2-C6 alkylene. In some embodiments, the linker comprises C4-C6 alkylene.

[0230] In some embodiments, each of L1is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-. -S(==O)-, -S(==O)2-, =CH-, -C( O)-, -C( O)O-, -OC(==O)-, -OC( O)O-, -C(==O)NRL-, - NRLC(==O)-, -OC(==O)NRL-, -NRLC(==O)O-, -NRLC(==O)NRL-, -NRLC(==S)NRL-, -CRL==N-, -N-CRL, - NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NR" S(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3- C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L1is -O-, -NR"-, -OP(=O)(ORL)O~, -S-, -S(=O)-, -S(= =0) 2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRT-, -C(:::O)NRLS(:::O)2-, or -S(:::O)2NRTC(:::O)-. In some embodiments, L1is -O-, -NH-, -S(::O)-, -S(:::O)2-, or -C(=O)-. In some embodiments, L1is -C(=O)NH- or -NHC(=O)-. In some embodiments, L1is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or un substituted C1-C12 heterocycloalkyl. In some embodiments, L1is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L1is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L1is substituted or unsubstituted C2-C30 alkenylene. In some embodiments, L1is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L1is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L1is substituted or unsubstituted C5-C12Attorney Docket No. 01277-0089-00PCT-RYZheteroalkylene.

[0231] In some embodiments, each of L2is independently -O-, -NRL-, -N(R1J)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRT-, -NRTC(=O)O-, -NRTC(=O)NRL-, -NR1C(=S)NRI-, -CR1=N-, -N=CRL, -NRLS(:::O)2-, -S(::::O)2NRL-, -C(:::O)NR2())-. -S(:::O)2NRLC(:::O)-, substituted or unsubstituted C3- C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, in some embodiments, L ’ is -O-, -NR1"-, -OP(=O)(ORL)O-, -S-, - S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRTC(=O)-. In some embodiments, L2is -O-, -Nil-, -S(=O)-, -S( O) -. or -C(:::O)-. In some embodiments, L2is -C(:::O)NH- or -NHC(:::O)-. In some embodiments, L is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted Ci-Ci2heterocycloalkyl. In some embodiments, L2is substituted or unsubstituted ary l or substituted or unsubstituted heteroaryl. In some embodiments, L2is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L2is substituted or unsubstituted C2-C30 alkenylene. In some embodiments, L2is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C5-C12 heteroalkylene.

[0232] In some embodiments, each of L3is independently -O-, -NR1'-, -N(R )2-, -OP(==O)(ORI)O-, -S-. -S(==O)-, -S(==O)2-, =CH-, -C( O)-, -C( 0)0-, -OC(==O)-, -OC(==O)O-, -C(:::O)NRL-, - NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, - NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NR“S(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L3is -O-, -NR“-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRI-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(==O)NRL-, -NRLC(==S)NRL-, -NRLS(===O)2-, -S( O)2NRL-, - C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-. In some embodiments, L3is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L3is -C(=O)NH- or -NHC(=O)-, In some embodiments, I.? is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted Cj -C12 heterocycloalkyl. In some embodiments, L3is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L3is substituted or unsubstituted C1-C30 alkylene. In some embodiments, I is substituted or un substituted C2-C30 alkenylene. In some embodiments, L is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L3is substituted orAttorney Docket No. 01277-0089-00PCT-RYZunsubstituted C5-C25 heteroalkylene, in some embodiments, L3is substituted or unsubstituted C5-C12 heteroalkylene. In some embodiments, L3is absent.

[0233] In some embodiments, each of L4is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRI-, - NRLC(==O)-, -OC( O)NRL-, -NRLC(==O)O-, -NRLC(==O)NRL-, -NRLC(==S)NRL-, -CRL==N-, -N-CRL, - NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NR" S(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L4is -O-, -NR"-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(= =0) 2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRT-, -C(:::O)NRLS(:::O)2-, or -S(:::O)2NRIC(:::O)-. In some embodiments, L4is -O-, NH-, -S(:::O)-, -S( O) or -C(=O)-. In some embodiments, L4is -C(=O)NH- or -NHC(=O)-. In some embodiments, L4is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L4is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L4is substituted or unsubstituted C1-C 0 alkylene. In some embodiments, L4is substituted or unsubstituted C2-C30 alkenylene. In some embodiments, L4is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L4is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L4is substituted or unsubstituted C5-C12 heteroalkylene. In some embodiments, L4is absent.

[0234] In some embodiments, each of L5is independently -O-, -NR1'-, -N(R")2-, -OP( O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, - NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, - RLS(::::O)2-, -S(:::O)2NRL-, -C(:::O)NR S(::0)2-, -S(::::O)2NRLC(::::O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, I? is -O-, -NR"-, -OP(=O)(ORJ)O-, -S-, -S(==O)-, -S(==O)2-, -C( O)-, -C( O)O-, -OC(===O)-, -OC(===O)O-, -C(==O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, - C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-. In some embodiments, I? is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L5is -C(=0)NH- or -NHC(=0)-. In some embodiments, L? is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L5is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L5IS substituted or unsubstituted C1-C30 alkylene. In some embodiments, L5is substituted or unsubstituted C2-C30 alkenylene. In some embodiments, L 'isAttorney Docket No. 01277-0089-00PCT-RYZsubstituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L3is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L5is substituted or unsubstituted C5-C12 heteroalkylene. In some embodiments, 17 is absent,

[0235] In some embodiments, at least one L1is unsubstituted C3-C20 alkylene.

[0236] In some embodiments, the linker comprises one or more of a substituted or unsubstituted Cg- Cio ryl, substituted or unsubstituted C5-C9 heteroaryl, a sterol, sulfonamide, phosphate ester, polyethylene glycol, or C3-C20 alkylene, or ammo acid residues.

[0237] In some embodiments, the linker comprises one or more selected from AEEA, AEEP, AEEEP, and AEEEEP groups. In some embodiments, the linker comprisesO (AEEA). In some embodiments, the linker compriseso0H(AEEP). In some embodiments, the linker comprisesOHHjN'(AEEEP). In some embodiments, the linker comprises" OjA (AEEEEP).N

[0238] In some embodiments, the linker is. In some embodiments, the linker is or comprises lysine. In some embodiments, the linker comprises C1-C12 alkylene. In some embodiments, the linker comprises C3-C9 alkylene. In some embodiments, the linker comprises C2-C8 alkylene. In some embodiments, the linker comprises 1 to 10 repeating ethylene glycol units. In some embodiments, the linker comprises 2 to 4 repeating ethylene glycol units. In some embodiments, the linker comprises 5 to 8 repeating ethylene glycol units. In some embodiments, tire linker comprises NH2-(CH2)n-COOH, wherein n is 1 to 12. In some embodiments, the linker comprises NH2-(CH2)2- COOH. In some embodiments, the linker comprises NH2-(CH2)3-COOH. In some embodiments, the linker comprises NH2-(CH2.)4-COOH. In some embodiments, the linker comprises NFE CH?,);- COOII. In some embodiments, the linker comprises NH2-(CH2) -COOII. In some embodiments, the linker comprises NH2-(CH2)?-COOH. In some embodiments, the linker comprises NH2-(CH2)g- COOH. In some embodiments, the linker comprises NH2-(CH2)IO-COOH. In some embodiments, the linker is absent.

[0239] In some embodiments, a linker of the present disclosure (e.g., a linker of Formula (II- 1), (II-Attorney Docket No. 01277-0089-00PCT-RYZla) or (II- lb)) comprises a structure of

[0240] In some embodiments, a linker of the present disclosure comprises a structure of

[0241] In some embodiments, a linker of the present disclosure (e.g., a linker of Formula (II- 1), (II-Attorney Docket No. 01277-0089-00PCT-RYZwherein each kl is independently 0 or an integer from 1 to 20; and each k2 is independently 0 or an integer from 1 to 15. In some embodiments, kl is 0. In some embodiments, kl is 1. In some embodiments, kl is 2. In some embodiments, kl is 3. In some embodiments, kl is 4. In some embodiments, kl is 5. In some embodiments, kl is 6. In some embodiments, kl is 7. In some embodiments, kl is 8. In some embodiments, kl is 9. In some embodiments, kl is 10. In some embodiments, kl is 11. In some embodiments, kl is 12. In some embodiments, kl is 13. In some embodiments, kl is 14. In some embodiments, kl is 15. In some embodiments, kl is 16. In some embodiments, kl is 17. In some embodiments, kl is 18, In some embodiments, kl is 19. In some embodiments, kl is 20. In some embodiments, k2 is 0. In some embodiments, k2 is 1. In some embodiments, k2 is 2. In some embodiments, k2 is 3. In some embodiments, k2 is 4. In some embodiments, k2 is 5. In some embodiments, k2 is 6. In some embodiments, k2 is 7. In some embodiments, k2 is 8. In some embodiments, k2 is 9. In some embodiments, k2 is 10, In some embodiments, k2 is 11. In some embodiments, k2 is 12. In some embodiments, k2 is 13. In some embodiments, k2 is 14. In some embodiments, k2 is 15.Attorney Docket No. 01277-0089-00PCT-RYZ

[0243] In some embodiments, the linker comprises a structure selected from:HN^Attorney Docket No. 01277-0089-00PCT-RYZ

[0244] In some embodiments, the linker comprises a structure selected from:Attorney Docket No. 01277-0089-00PCT-RYZAttorney Docket No. 01277-0089-00PCT-RYZAttorney Docket No. 01277-0089-00PCT-RYZOHOY. \ At H < wherein each kl and k2 is independently 0 or an integer selected from 1 to 20.

[0246] In some embodiments, kl is selected from 0-12. In some embodiments, kl is 0. In some embodiments, kl is 1. In some embodiments, kl is 2. In some embodiments, kl is 3. In some embodiments, kl is 4. In some embodiments, kl is 5. In some embodiments, kl is 6. In some embodiments, kl is 7. In some embodiments, kl is 8. In some embodiments, kl is 9. In some embodiments, kl is 10. In some embodiments, k2 is selected from 0-12. In some embodiments, k2 is 0. In some embodiments, k2 is 1. In some embodiments, k2 is 2. In some embodiments, k2 is 3. In some embodiments, k2 is 4. In some embodiments, k2 is 5. In some embodiments, k2 is 6. In some embodiments, k2 is 7. In some embodiments, k2 is 8. In some embodiments, k2 is 9. In some embodiments, k2 is 10.Metal Chelator

[0247] In one aspect, described herein are conjugates that comprise a metal chelator that is configured to bind with a radionuclide. The metal chelator can refer to a moiety of the conjugate that is configured to bind with a radionuclide. In some embodiments, a conjugate described herein comprises two or more independent metal chelators, e.g., 2, 3, 4, 5, or more metal chelators. In some embodiments, a conjugate described herein comprises two metal chelators, which can be the same or different. In some embodiments, a conjugate described herein comprises two or more metal chelators. In some embodiments, the conjugate comprises two radionuclides bound to the metal chelators. The metal chelator can be attached to the linker or the peptide through any suitable group / atom of the chelator.

[0248] In some embodiments, the metal chelator is capable of binding a radioactive atom. The binding can be direct, e.g., the metal chelator can make hydrogen bonds or electrostatic interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, or is, 2,2',2",2"'-(l,4,7,l O-Tetraazacyclododecane- 1,4,7, 10-tetrayl)tetraacetic acid (DOTA) or l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA). In some embodiments, the metal chelator comprises a macrocycle, e.g., a macrocycle comprising an O and / or a N, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTP A, TETA, DOS A, PCTA, or desferrioxamine.Attorney Docket No. 01277-0089-00PCT-RYZ

[0249] In some embodiments, the metal chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more N, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise S, In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an O and / or an N. In some embodiments, the metal chelator is a ring that includes 3 or more N, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is polydentate.

[0250] In some embodiments, a metal chelator described herein is selected from: DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2 -DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2 -NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, Hl -MACROP A, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA.

[0251] In some embodiments, a metal chelator described herein has a structure ofAttorney Docket No. 01277-0089-00PCT-RYZembodiments, a metal chelator described herein has a structure of (DOTA).In some embodiments, a metal chelator described herein has a structureof (NOTA).

[0252] In some embodiments, a metal chelator described herein comprises a cyclic chelating agent. Exemplary cyclic chelating agents include, but are not limited to, AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, II3IIP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-lpy, p-SCN-Bn-DOTA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEIIA, HEIIA-NCS, p-SCN-Bn-HEIIA, DTP A, CHX-A"-DTPA, p-NH2-Bn-CHX-A"-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-BnlB-DTPA, p-SCN-Bn-1B4M-DTPA, p-SCN-Bn-CHX-A"-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H2L1, H3L4, H2azapa, H4decapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4octapa, p-SCN-Bn-Attorney Docket No. 01277-0089-00PCT-RYZH4octapa, TTHA, p-NO2-Bn-neunpa, H4Loctox, H2macropa, H2bispa2, H4phospa, H6phospa, p-SCN-Bn-H4phospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycup1A1B, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr- NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA- monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, Lpy, LI, L2, L3, and EuK-106. In some embodiments, the metal chelator is DOTA, TRITA, TETA, DOTA -MA, DO3A-HP, DOIMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, p-NCS-DOTA, p-NCS-PADOTA, BAT, DO3TMP-Monoamide, p-NCS-TRITA, NOTA, or CFIX-A"-DTPA. In some embodiments, a metal chelator described herein comprises an acyclic chelating agent. Exemplary acyclic chelating agents include, but are not limited to, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA. In some embodiments, a metal chelator described herein comprises DOTA, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, D03A, D02A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, D0TA-4AMP, or NOTP. In some embodiments, a metal chelator described herein comprises H4pypa, HLoctox, H4octapa, p-NO2-Bn-neunpa, p-SCN-Bn-Hmeunpa, TTHA, ‘Bu4pypa-C7-NHS, H4neunpa, H2macropa, HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, D03AMBu, DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn-PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATA”, THP, HEHA, or HBED.

[0253] In some embodiments, the metal chelator is DO3A. In some embodiments, the metal chelator is PEPA. In some embodiments, the metal chelator is EDTA, In some embodiments, the metal chelator is CHX-A"-DTPA. In some embodiments, the metal chelator is HEHA. In some embodiments, the metal chelator is DOTMP. In some embodiments, the metal chelator is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelator is macropa. In some embodiments, the metal chelator is macropa-NCS. In some embodiments, the metal chelator is H4pypa. In some embodiments, the metal chelator is H4octapa. In some embodiments, the metal chelator is H4CHXoctapa. In some embodiments, the metal chelator is DOTP. In some embodiments, the metal chelator is crown.

[0254] In some embodiments, the metal chelator is DOTA. In some embodiments, the metal chelator is a chiral derivative of DOTA. Exemplary’ chiral DOTA chelators are described in Dai et al., Nature Communications (2018) 9:857. In some embodiments, the metal chelator is 2,2',2",2"'-((2S,5S,8S, HS)-2,5,8, 11 -tetramethyl- 1, 4,7, 10-tetraazacyclododecane-l, 4,7, 10-tetrayl)tetraacetic acid. In someAttorney Docket No. 01277-0089-00PCT-RYZembodiments, the metal chelator has a structure ofO. In some embodiments, the metal chelator is 2,2',2",2'"-((2S,5S,8S,llS)-2,5,8,ll-tetraethyl-l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a

[0255] In some embodiments, the metal chelator has a structure of O wherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain. In some embodiments,Othe metal chelator has a structure ofO wherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain.

[0256] In some embodiments, the conjugate comprises DOTA. In some embodiments, the conjugateAttorney Docket No. 01277-0089-00PCT-RYZcomprises a DOTA derivative such as p-SCN-Bn-DOTA and MeO-DOTA-NCS. In some embodiments, the conjugate comprises two independent metal chelators, and at least one or both are DO TA. The structures of some exemplary’ metal chelators are illustrated in FIGs, 5-19 (without showing the attachment points). Exemplary metal chelators are also illustrated in FIGs. 1A, 2 A, 3 A, and 4A (attachment point shown as a squiggly line) and FIGs. IB, 2B, 3B and 4B (except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle). In some embodiments, a conjugate comprises a metal chelator of FIG. 1 A. In some embodiments, a conjugate comprises a metal chelator of FIG. 2A. In some embodiments, a conjugate comprises a metal chelator of FIG. 3 A. In some embodiments, a conjugate comprises a metal chelator of FIG. 4A. Exemplary metal chelators are further described in WO2012 / 174136; US20130183235A1; US20120219495A1; Ramogida and et al., EJNMMI radiopharm. chem. 4, 21 (2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018; Li et al., Bioconjugate Chem. 2019, 30, 5, 1539-1553; and Baranyai et al., Eur. J. Inorg. Chem. 36-56 (2020), each of which is incorporated by reference in its entirety.

[0257] A metal chelator such as DOTA can interact with a radionuclide (e.g.,177Lu or225Ac) via one or more functional groups and / or atoms. For example, a metal chelator can interact with a radionuclide via nitrogen and / or oxygen atoms. As another example, a metal chelator can interact with a radionuclide via carbonyl, carboxylic acid, amino, and / or amide groups of the metal chelator. In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustratedIn some embodiments, the interaction of a metal chelator and aradionuclide of the conjugates disclosed herein can be illustrated assome embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosedAttorney Docket No. 01277-0089-00PCT-RYZoherein can be illustratedas In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as0 or O. In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated asIn some embodiments, the interaction of a metal chelator and aradionuclide of the conjugates disclosed herein can be illustratedas some embodiments, the radionuclide exists in a positive oxidation state e.g.,225Ac3+, ’‘^Lu33. In some embodiments, for example in certain aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3’,177Lu3+. In some embodiments, for example in certain acidic aqueous conditions, theAttorney Docket No. 01277-0089-00PCT-RYZradionuclide exists in a salt form, e.g., as225Ac2",177Lu3+. In some embodiments, the conjugate is in a salt form. In some embodiments, one or more of the carboxylic acid groups of the conjugate may exist as carboxylate anions. In some embodiments, one or more of the carboxylate anions of the conjugate may coordinate to the radionuclide. A person of ordinary skill would appreciate that the dissociation of an acid can depend on the pH value of the environment and its pK value. Accordingly, in some embodiments, a conjugate described herein can exist in a completely ionized, partially ionized or non¬ ionized form.Radionuclides

[0258] In one aspect, disclosed herein are radiopharmaceuticals comprising a radionuclide. In some embodiments, the radionuclide is chelated or bound to a metal chelator. In some embodiments, the radionuclide is covalently bound to the conjugate. Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety (e.g., binding peptide), etc. Radionuclides that undergo a-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo p-decay emit energetic electrons from their nuclei. Some radionuclides can also undergo electron capture and emit auger electrons. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Table 10 below illustrates some properties of exemplary radionuclides.Table 10. Exemplary radionuclidesTherapeutics Therapeutics (Tx) (Tx) Emission / Emission / Radionuclide or Radionuclide or Decay DecayDiagnostics Diagnostics (Dx) (Dx) Ac-225 Alpha Tx 1-131 Beta Tx As-70 Positron Dx In-111 Photon / Electron Capture Dx As-71 Positron Dx Lu- 177 Beta / Photon Tx / Dx As-72 Positron Dx Mn-52 Positron Dx ElectronAs-73 Dx Pb-212 Alpha Tx CaptureAs-74 Positron Dx Pm-153 Beta Tx As-76 Beta Tx Po-213 Alpha Tx As-77 Beta Tx Ra-223 Alpha Tx At-211 Alpha Tx Ra-224 Alpha Tx Bi-209 Alpha Tx Re-186 Beta / Photon Dx Bi-212 Alpha Tx Re-188 Beta / Photon Dx Bi-213 Alpha Tx Rh-105 Beta Tx Br-76 Positron Dx Sm-153 Beta / Photon Tx / Dx ElectronCe-134 Dx Sc-44 Beta / Positron DxCaptureAttorney Docket No. 01277-0089-00PCT-RYZTherapeutics Therapeutics (Tx) (Tx) Emission / Emission / Radionuclide or Radionuclide or Decay DecayDiagnostics Diagnostics (Dx) (Dx) Cu-61 Positron Dx Tb-149 Alpha Tx Cu-62 Positron Dx Tb-152 Positron Dx Cu-64 Positron Dx Tb-161 Beta / Photon Tx / Dx Photon / Gamma / IsomericCu-67 Beta Tx Tc-99m Dx TransitionF-18 Positron Dx Th-227 Alpha Tx Fr-223 Alpha Tx Th-229 Alpha Tx Ga-67 Beta / Photon Dx Ti-45 Positron Dx Ga-68 Positron Dx Tm-167 Beta / Electron Capture Tx Gd-148 Alpha Tx Y-86 Positron Dx Ho- 166 Beta / gamma Tx / Dx Y-90 Beta / Photon Tx / Dx Electron1-123 Dx Yb-175 Beta Tx Capture / photon1-124 Positron Dx Zr-89 Positron Dx Electron1-125 DxCapture

[0259] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from Table 10.

[0260] In some embodiments, the radiopharmaceutical conjugate described herein comprises one or more independent radionuclides. In some embodiments, the radiopharmaceutical conjugate comprises two radionuclides. In some embodiments, each of the one or more radionuclides is bound to the metal chelator of the radiopharmaceutical conjugate. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelator. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0261] In some embodiments, the radiopharmaceutical conjugate described herein comprises an alpha particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises an alpha-particle emitting radionuclide bound to the metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 (225Ac), radium-223 (223Ra), radium-224 (224Ra), bismuth-209 (209Bi), bismuth-213 (213Bi), gadolinium -148 (148Gd), terbium-149 (149Tb), polonium-213 (213Po), francium-223 (223Fr), thorium-227 ( Th). thorium-229 ( Th). or lead-212 (212Pb). In some embodiments, the alpha particle -emitting radionuclide is selected from225Ac,223Ra.209Bi,213Bi,148Gd,149Tb,213Po.223Fr,227Th,229Th, and212Pb. In some embodiments, the alpha particle¬ emitting radionuclide is Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213. In some embodiments, the alpha particle-emitting radionuclide is225Ac. In some embodiments, the alpha particle -emitting radionuclide is213Bi. In some embodiments, the alpha particle-emitting radionuclide is212Bi. In some embodiments, the alpha particle -emitting radionuclideAttorney Docket No. 01277-0089-00PCT-RYZis212Pb. In some embodiments, the alpha particle -emitting radionuclide is224Ra. In some embodiments, the alpha particle -emitting radionuclide is223Ra. In some embodiments, the alpha particle-emitting radionuclide is227Th. In some embodiments, the alpha particle-emitting radionuclide is149Tb. In some embodiments, the conjugate comprises225Ac. In some embodiments, the conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)177Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)225Ac. In some embodiments, the radionuclide is177Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the conjugate comprises two177Lu radionuclides. In some embodiments, the radionuclide is a non-carrier-added radionuclide. In some embodiments, the radionuclide is a pseudo-radiometal. In some embodiments, the pseudo-radiometal is aluminum -[18F]fluoride ([18F]AlF) complex.

[0262] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from62Cu,64Cu,67Cu,90Y,109Pd, “’Ag,134Ce,149Pm,153Sm,166Ho,99mTc,67Ga,68Ga,111In,90Y,177Lu,186Re,188Re,197Au,195Au,199Au,105Rh,165Ho,161Tb,149Pm,153Pm, ^Sc,47Sc,213Po,212Pb,209Bi,212Bi,213Bi,225Ac,117mSn,67Ga,149Tb,152Tb.167Tm,175Yb,223Ra,223Fr,227Th,229Th,201Tl,148Gd,160Gd, ’148Nd,89Sr, and89Zr. In some embodiments, the radionuclide is selected from62Cu,64Cu,67Cu,68Ga,89Zr,90Y,99mTc,105Rh, In,134Ce,148Gd,149Tb,152Tb,153Pm,l67Tm,i75Yb,177Lu,209Bi,212Pb,213Po,213Bi,223Ra.223Fr,227Th,225Ac, and229Th. In some embodiments, the radionuclide is225Ac, In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,2O9T1,209Pb, or209Bi. In some embodiments, the radiopharmaceutical conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is177Lu. In some embodiments, the radiopharmaceutical conjugate comprises two177Lu radionuclides.

[0263] In some embodiments, the radiopharmaceutical conjugate described herein comprises a beta particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a beta particle-emitting radionuclide bound to the metal chelator. In some embodiments, the beta particle-emitting radionuclide is copper-67, rhodium- 105, ytterbium- 175, thulium- 167, promethium-153, yttrium-90, samarium- 153, or lutetium- 177. In some embodiments, the beta particle emitting radionuclide is copper-67, yttrium-90, samarium- 153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is lutetium-177. In some embodiments, the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111.

[0264] In some embodiments, the radiopharmaceutical conjugate described herein comprises a gamma particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a gamma particle-emitting radionuclide bound to the metal chelator. In some embodiments, the gamma particle-emitting radionuclide is indium- 111 or tin-117m.

[0265] In some embodiments, the radiopharmaceutical conjugate described herein comprises a positron particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron particle-emitting radionuclide bound to the metal chelator. In someAttorney Docket No. 01277-0089-00PCT-RYZembodiments, the positron -emitting radionuclide is gallium-68, copper-61, copper-62, copper-64, zirconium-89, or terbium-152. In some embodiments, the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152, In some embodiments, the radionuclide is zirconium-89. In some embodiments, the radionuclide is gallium-68.

[0266] In some embodiments, a conjugate described herein comprises a radionuclide suitable for imaging or diagnostic purposes. In some embodiments, the radionuclide suitable for imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb,68Ga,11‘in, and "mTc. In some embodiments, the radionuclide is suitable PET imaging. In some embodiments, the radionuclide suitable for PET imaging is selected from62Cu,64Cu,89Zr,134Ce, Tb. and68Ga. In some embodiments, the radionuclide is suitable for SPECT imaging. In some embodiments, the radionuclide suitable for SPECT imaging is selected from111In and "mTc,

[0267] In some embodiments, radiopharmaceutical conjugates described herein do not contain any hot radionuclide, i.e., a cold conjugate. For example, in some cases, a radionuclide can be replaced with a surrogate (e.g.,225Ac replaced with lanthanum) fortesting and experimental purposes. In some embodiments, hot lutetium (Lu-177) is replaced with a cold lutetium (Lu-175).

[0268] In some embodiments, a radiopharmaceutical conjugate described herein comprises a covalently bound radionuclide and optionally a linker. In some embodiments, the linker can comprise a residualizing agent or a non-residualizing agent. A radionuclide can be attached to a peptide or a linker through a residualizing agent or a non -residualizing agent. In some embodiments, the radionuclide is covalently attached to the peptide or the linker through a residualizing agent. In some embodiments, the residualizing agent is SGMIB or SIPC. In some embodiments, the radionuclide is covalently attached to the peptide or the linker through a residualizing agent. In some embodiments, the non-residualizing agent is N-succinimidyl-4-iodobenzoate (PIB). In some embodiments, a radionuclide is covalently bound to the residualizing agent or the non-residualizing agent. In some embodiments, the radionuclide is covalently bound to the residualizing agent. Procedures and methods for synthesis of covalently bound residualizing agents are described in US 9,839,704 which is herein incorporated by reference in its entirety.

[0269] In some embodiments, the residualizing agent is a tetrapeptide IMP-R4. IMP-R4 can be represented as MCC-Lys(MCC)-Lys(Z)-d-Tyr-d-Lys(X)-OH (SEQ ID NO: 621), where MCC is 4- (N-nialeimidomethyl)-cyclohexane-l -carbonyl and Z is l-((4-thiocarbonylamino)benzyl)-DTPA. In some embodiments, the radionuclide131I is linked to linker or peptide via131I-IMP-R. In some embodiments, the residualizing agent is a tetrapeptide IMP-R3. In some embodiments, the residualizing agent is a tetrapeptide IMP-R5. In some embodiments, the residualizing agent is a tetrapeptide IMP-R6. In some embodiments, the residualizing agent is a tetrapeptide IMP-R7. In some embodiments, the residualizing agent is a tetrapeptide IMP-R8. Exemplary residualizing and non-residualizing agents are further illustrated in Stein R, et al. Improved iodine radiolabels for monoclonal antibody therapy, Cancer Res. 2003;63: 111-118; Reist CJ, et al. Radioiodination ofAttorney Docket No. 01277-0089-00PCT-RYZinternalizing monoclonal antibodies using N-succinimidyl-5-iodo-3-pyridinecarboxylate, Cancer Res.1996:56:4970-4977; Ali SA, et al. Improving the tumor retention of radioiodinated antibody: aryl carbohydrate adducts. Cancer Res. 1990;50(suppl):783s-788s; and Serengulam V. Govindan, et al., Clinical-Scale Radiolabeling of a Humanized Anticarcinoembryonic Antigen Monoclonal Antibody, hMN-14, with Residualizing 1311 for Use in Radioimmunotherapy, Journal of Nuclear Medicine January 2005, 46 (1) 153-159.Labeled compounds

[0270] In some embodiments, the conjugates described herein exist in their isotopically -labeled forms, in some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled conjugates as pharmaceutical compositions. For example, the conjugates described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the conjugates described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the conjugates described herein may be artificially enriched in one or more isotopes selected from deuterium (2H), tritium (3H), and / or carbon- 14 (14C). All isotopic variations of the conjugates of the present disclosure are encompassed within the scope of the present disclosure. Examples of isotopes that can be incorporated into conjugates described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S, ’18F, and36Cl, respectively. Conjugates described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled conjugates, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled conjugate or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

[0271] In some embodiments, the conjugates described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0272] In some embodiments, the peptides, conjugates, and radiopharmaceuticals described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In someAttorney Docket No. 01277-0089-00PCT-RYZembodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. As used herein, a "‘pharmaceutically acceptable salt” refers to any salt of a compound that is useful for therapeutic purposes of a subject.

[0273] In some embodiments, the peptides, conjugates, and radiopharmaceuticals described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0274] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the peptides, conjugates, and radiopharmaceuticals described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropi onate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 -napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.

[0275] Further, the peptides, conjugates, and radiopharmaceuticals described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,Attorney Docket No. 01277-0089-00PCT-RYZglutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0276] In some embodiments, those peptides, conjugates, and radiopharmaceuticals described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, w ith ammonia, or w ith a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

[0277] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the peptides, conjugates, and radiopharmaceuticals described herein also include the quatemization of any basic nitrogen -containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0278] In some embodiments, the peptides, conjugates, and radiopharmaceuticals described herein exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0279] Solvates contain either stoichiometric or non -stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization w ith pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the peptides, conjugates, and radiopharmaceuticals described herein can be conveniently prepared or formed during the processes described herein. In addition, the peptides, conjugates, and radiopharmaceuticals provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Accordingly, one aspect of the present disclosure pertains to hydrates and solvates of peptides, conjugates, and radiopharmaceuticals and / or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-lnfrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like.Preparation of the Peptides and Conjugates

[0280] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (MiltonAttorney Docket No. 01277-0089-00PCT-RYZPark, UK), Avocado Research (Lancashire, U. K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U. K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U. K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U. K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury', CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0281] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry'”, John Wiley & Sons, Inc., New' York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L, Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G, “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry'” 2nd Edition (1993) Wiley-lnterscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry' of Functional Groups” John Wiley & Sons, in 73 volumes.

[0282] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses,Attorney Docket No. 01277-0089-00PCT-RYZwhere many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P, H, Stahl & C. G, Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0283] In one aspect, described herein is a method of making a conjugate that comprises a cyclic peptide, a metal chelator, optionally a linker, and optionally a radionuclide such as177Lu or225Ac. In some embodiments, the conjugate is prepared by one or more of the following steps: (a) synthesizing the peptide sequence by solid phase peptide synthesis; (b) cyclizing the peptide by forming an intramolecular non-peptide bond; (c) coupling the metal chelator to the peptide; (d) and optionally- labeling the conjugate with a radionuclide. In some embodiments, steps (a), (b), (c) and (d) are performed in the recited order. In some embodiments, synthesizing the peptide comprises synthesizing the peptide sequence in a protected form and performing a de-protecting reaction. In some embodiments, cyclizing the peptide comprises forming a non-peptide bond between the N-terminus and the C-tenninus of the peptide. In some embodiments, cyclizing the peptide comprises forming a non-peptide bond between the N-terminus and a cysteine or homocysteine of the peptide. In some embodiments, cyclizing the peptide comprises forming a ring closing group selected from -C(:::O)-CH2-, -C(:::O)-CH2-S-, -S-, -CH=CH-, -NH-, -maleimide-S-, -C(:::O)-CH2-NH-, and -C(:::O)-CH2-O-. In some embodiments, cyclizing the peptide comprises forming a ring closing group of Table 4B. In some embodiments, cyclizing the peptide comprises reacting a pair of functional groups or amino acids described in Table 4C. In some embodiments, solid phase peptide synthesis can be replaced with other suitable peptide synthesis methods known in the art.Peptide Production

[0284] The peptide of the present technology may be produced by, for example, any known method for producing a peptide, such as the following:• a chemical synthesis method such as a liquid phase method, a solid phase method, a hybrid method combining a liquid phase method and a solid phase method, or the like;« a genetic recombination method; or the like.

[0285] In some of the instances where the peptide of the present technology is produced by a chemical synthesis method, it can be said that the peptide of the present technology is a synthetic peptide,

[0286] In the solid phase method, for example, a hydroxy group of a resin having a hydroxy group and a carboxy group of a first amino acid (normally a C -terminal amino acid of a target peptide) in which an a-amino group is protected by a protecting group are subjected to an esterification reaction. For the esterification catalyst, a known dehydrating and condensing agent such as 1-mesitylenesulfonyl-3-nitro-l, 2, 4-triazole (MSNT), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIPCDI) may be used.

[0287] Next, the protecting group of the a-amino group of the first amino acid is removed, a secondAttorney Docket No. 01277-0089-00PCT-RYZamino acid in which all functional groups except the carboxy group of the main chain are protected is added, and the carboxy group is activated, binding the first and second amino acids. Furthermore, the a-amino group of the second amino acid is deprotected, a third amino acid in which all functional groups except the carboxy group of tire main chain are protected is added, the carboxy group is activated, binding the second and third amino acids. This is repeated, and after a peptide having a target length is synthesized, all of the functional groups are deprotected.

[0288] Examples of the resin for solid-phase synthesis include Merrifield resin, MBHA resin, Cl-Trt resin, SASRIN resin, Wang resin, Rink amide resin, HMFS resin, Amino-PEGA resin (Merck KGaA), HMPA-PEGA resin (Merck KGaA), and the like. These resins may be used after being washed using a solvent (dimethylformamide (DMF), 2 -propanol, methylene chloride, and the like). A peptide chain can be cleaved from the resin by treating it with an acid such as TFA or hydrogen fluoride (I IF).

[0289] Examples of the protecting group of the a-amino group include a benzyloxycarbonyl (Cbz or Z) group, tert-butoxycarbonyl (Boc) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyl group, allyl group, allyl oxy carbonyl (Alloc) group, and the like. The Cbz group may be deprotected by a treatment using hydrofluoric acid, hydrogenation, or the like, the Boc group may be deprotected by a treatment using trifluoroacetic acid (TFA), and the Fmoc group may be deprotected by a treatment using pipericine or pyrrolysine.

[0290] Examples, such as methyl ester, ethyl ester, allyl ester, benzyl ester, tert-buty l ester, cyclohexyl ester, and the like may be used to protect the a-carboxy group.

[0291] As other functional groups of an amino acid, the hydroxyl group of serine or threonine can be protected with a benzyl group or a tert-butyl group and the hydroxyl group of tyrosine can be protected with a 2 -bromobenzyloxy carbonyl group or a tert-buty l group. The amino group of a lysine side chain or the carboxyl group of glutamic acid or aspartic acid can be protected in a manner similar to the a-amino group or a-carboxy 1 group.

[0292] Activation of the carboxy group may be performed using a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCDI), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or WSC), ( IH-benzotri azole- 1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1 -[bis(dimethylamino)methyl]-lH-benzotriazolium-3-oxide hexafluorophosphate (HBTU), and the like.

[0293] Cleavage of the peptide chain from the resin may be performed by treating the peptide chain using an acid such as TFA, hydrogen fluoride (HF), or the like.

[0294] Production of a peptide by a gene recombination method (translation / synthesis system) may be performed using a nucleic acid encoding the peptide. The nucleic acid encoding the peptide may be DNA or RNA.

[0295] The nucleic acid encoding the peptide may be prepared by a known method or a method equivalent thereto. For example, the peptide may be synthesized by an automated synthesizer. AAttorney Docket No. 01277-0089-00PCT-RYZrestriction enzyme recognition site may be added to insert the obtained DNA into a vector.Alternatively, a base sequence encoding an amino acid sequence for splicing a formed peptide chain using an enzyme or the like may be incorporated. The peptide obtained may be converted from a free peptide to a salt thereof or from a salt thereof to a free peptide by a known method or a method based thereon.

[0296] As described above, when the peptide is fused to a cell-penetrating peptide or the like, the nucleic acid also includes a nucleic acid encoding the cell-penetrating peptide.

[0297] A chimeric protein expression method for expressing the target peptide as a chimeric peptide of another peptide may also be used to suppress degradation by a host-derived protease. In this case, a nucleic acid encoding the target peptide and the peptide bound thereto may be used as the nucleic acid.

[0298] Subsequently, an expression vector is prepared using the nucleic acid encoding the peptide. The nucleic acid may be digested as is or by a restriction enzyme, and alternatively, the nucleic acid may be inserted downstream of a promoter of the expression vector by adding a linker, or the like. Examples of the vector include an Escherichia coli-AcmcA plasmid (pBR322, pBR325, pUC12, pUC13, pUC18, pUC19, pUCl 18, pBluescript II, and the like), a Bacillus suhtilis-Aemc plasmid (pUBl 10, pTP5, pC1912, pTP4, pE194, pC194, and the like), a yeast-derived plasmid (pSH19, pSH15, YEp, YRp, Yip, YAC, and the like), a bacteriophage (e phage, M13 phage, and tire like), a virus (retrovirus, vaccinia virus, adenovirus, adeno-associated virus (AAV), cauliflower mosaic virus, tobacco mosaic virus, baculo virus, and the like), a cosmid, and the like.

[0299] The promoter may be selected appropriately according to the type of host. When the host is an animal cell, for example, a promoter derived from SV40 (simian virus 40) or a promoter derived from CMV (cytomegalovirus) may be used. When the host is Escherichia col, a trp promoter, a T7 promoter, a lac promoter, or the like may be used.

[0300] The expression vector may incorporate, for example, a DNA replication starting point (ori), a selective marker (antibiotic resistance, auxotrophy, or the like), an enhancer, a splicing signal, a poly -A addition signal, a nucleic acid encoding a tag (FLAG, HA, GST, GFP, or the like), or the like.

[0301] Next, an appropriate host cell is transformed by the expression vector. The host may be appropriately selected in relation to the vector. Examples such as Escherichia coli. Bacillus subtilis Bacillus)', yeast, insects or insect cells, animal cells, or the like may be used as the host. As the animal cells, for example, HEK293T cells, CHO cells, COS cells, myeloma cells, HeLa cells, and Vero cells may be used. Transformation may be carried out according to a known method, such as a lipofection method, a calcium phosphate method, an electroporation method, a microinjection method, a gene gun method, or the like depending on the type of host. The target peptide is expressed by culturing a transformant according to a conventional method.

[0302] As for purification of the peptide from the transformant culture, cultured cells are recovered and then suspended in an appropriate buffer solution, followed by disruption of cells by a methodAttorney Docket No. 01277-0089-00PCT-RYZsuch as sonication, freeze-thawing, or the like, and then a crude extract is obtained by centrifugation or filtration. When the peptide is secreted into the culture solution, a supernatant is recovered.

[0303] Purification of the crude extract or the culture supernatant may also be performed by a known method or a method equivalent thereto (for example, salting-out, dialysis, an ultrafiltration method, gel filtration method, SDS-PAGE method, ion exchange chromatography, affinity chromatography, reversed-phase high-performance liquid chromatography, and the like).

[0304] The obtained peptide may be converted from a free body to a salt or from a salt to a free body by a known method or a method equivalent thereto.

[0305] In one aspect, the translation / synthesis system may be a cell-free translation system.According to the cell-free translation system, a highly pure form of an expression product can generally be obtained without purification. The cell-free translation system includes, for example, a ribosome protein, an aminoacyl-tRNA synthase (ARS), a ribosome RNA, an amino acid, rRNA, GTP, ATP, a translation initiation factor (IF), an elongation factor (EF), a release factor (RF), and a ribosome regeneration factor (RRF), or another factor required for translation. An Escherichia coli extract or a wheat embryo extract may be added to increase expression efficiency. In addition, a rabbit red blood cell extract or an insect cell extract may be added.

[0306] By continuously supplying energy to a system including these using dialysis, a protein of several hundred ug to several mg / mL may be produced in a non-limiting manner. The system may include an RNA polymerase to concurrently perform transcription of genomic DN A. Examples of commercially available cell-free translation systems that may be used include RTS- 100 (registered trademark) by Roche Diagnostics K. K., PETRE System by GeneFrontier Corporation, PURExpress In vitro Protein Synthesis Kit by New' England Biolabs Inc., and the like for a system derived from Escherichia coli, and a system by ZOIGENE, CellFree Sciences Co., Ltd., or the like for a system using wheat embryo extract.

[0307] In the cell translation system, artificial aminoacyl-tRNA may be used and a desired amino acid or hydroxy acid may be linked (acylated) to a tRNA in place of an aminoacyl-tRNA synthesized by a natural aminoacyl-tRNA synthase. The aminoacyl-tRNA may be synthesized using an artificial ribozyme.

[0308] An example of the ribozyme includes a flexizyme (flexizyme) (H. Murakami, H. Saito, and H. Suga, (2003), Chemistry & Biology, Vol. 10, 655-662; and WO 2007 / 066627 and the like), all incorporated herein by reference. Flexizymes are also known under the names of prototype flexizyme (Fx), new'ly modified dinitrobenzyl flexizyme (dFx), enhanced flexizyme (eFx), aminoflexizyme (aFx), and the like.

[0309] A desired codon may be translated in association w ith the desired amino acid or hydroxy acid by using the tRNA produced by flexizyme and to which the desired amino acid or hydroxy acid is linked. A specialty amino acid may be used as the desired amino acid. For example, an unnatural amino acid required for the above circularization may also be introduced into the binding peptide byAttorney Docket No. 01277-0089-00PCT-RYZthis method.

[0310] Various methods commonly used in the technical field may be used for chemical synthesis of the peptide, including, for example, stepwise solid-phase synthesis, semisynthesis of peptide fragments undergoing conformationally supported religation, and chemical ligation. Synthesis of the peptide is chemical synthesis using various solid phase technologies described in, for example, K. J. Jensen, P. T. Shelton, S. L. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013, and the like. A preferable strategy is based on a combination of an Fmoc group capable of temporarily protecting the a-amino group and being selectively removed using a base, and a protecting group that temporarily protects a side chain functional group and is stable under Fmoc deprotection conditions. Selection of this kind of general peptide side chain is known according to the aforementioned Peptide Synthesis and Applications, 2nd Edition; G, B. Fields, R, L. Noble, Solid Phase Peptide Synthesis Utilizing 9-Fluorenylmethoxycarbonyl Amino Acids, Int. J. Peptide Protein Res. 35, 1990, 161-214, and the like; however, preferable peptide side chain protecting groups include, for example, a benzyl group or a tert-butyl group and a trityl (Tit) group for the hydroxy group of serine or threonine; a 2-bromobenzyloxycarbonyl group or a tert-buty l group for the hydroxy group of tyrosine; a Boc group, a methyltetrazole thiol (Mtt) group, an Alloc group, and an ivDde group for the amino group of the lysine side chain; a Trt group or a Boc group for the imidazole group of histidine; a 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group (Pbf) group for the guanidyl group of arginine; a tert-butyl group, an allyl group, and a 3 -methylpentane (Mpe) group for carboxyl groups, such as glutamic acid and aspartic acid; a Trt group for the carboxamide group of glutamine or asparagine; or a Trt group and a monomethoxytrityl (Mmt) group for the thiol group of cysteine.[003111 The peptide may be synthesized by a stepwise method on the solid-phase resin described above. The C-terminal amino acid to be used and all of the amino acids or peptides to be used for synthesis must be selectively removed during the process of synthesizing the a-amino protecting group. Preferably, the solid -phase resin described above is used, and once a C-terminal carboxyl group of a peptide having its N-terminal properly protected by Fmoc or the like or a C-terminal carboxyl group of an amino acid having its N-terminal protected by Fmoc is made into an activated ester by an appropriate reagent, this is then added to the amino group on the solid-phase resin to start. Subsequent elongation of the peptide chain may be achieved by removing the N-terminal protecting group (Fmoc group) then successively repeating condensation of the protected amino acid derivative according to the amino acid sequence of the target peptide. Note that these may release the target peptide in a final stage. Examples of releasing conditions are given in Teixeira, W. E. Benckhuijsen, P. E. de Koning, A. R. P. M. Valentijn, J. W. Drijfhout, Protein Pept. Lett., 2002, 9, 379-385, and the like, and the peptide may be released in a TFA solution containing water / silyl hydride / thiol as a scavenger in TFA. Typical examples include TFA / Water / TIS / DODT (volume ratio 92.5:2.5:2.5:2.5).

[0312] Synthesis of the peptide described in the present specification may be carried out using a single or multi-channel peptide synthesizer, for example, a Liberty Blue synthesizer from CEMAttorney Docket No. 01277-0089-00PCT-RYZCorporation, a Syro I synthesizer or a successor machine thereof from Biotage Japan, Ltd., or the like.

[0313] Activation of the carboxy group may be performed using a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or WSC), (IH-benzotriazole-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-[bis(dimethylamino)methyl]-1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU), and the like.

[0314] Cyclization of the peptide may be carried out according to a known method. In a nonlimiting manner, by designing the peptide to comprise two or more cysteine residues, for example, a cyclic structure may be formed by a disulfide bond after translation. Furthermore, according to the method of Goto et al. (Y. Goto, et al. ACS Chem. Biol. 3 120-129 (2008)), a peptide having a chloroacetyl group at its N-terminal may be synthesized by genetic code reprogramming technology and may also be circularized by disposing a cysteine residue containing a sulfur molecule in the peptide. Thus, a mercapto group spontaneously performs a nucleophilic attack on the chloroacetyl group after translation, and the peptide is circularized by thioether binding. Other amino acid combinations that bind to form a ring may be disposed within the peptide and circularized by genetic code reprogramming technology. Alternatively, circularization may be carried out by disposing an L- 2 -aminoadipic acid residue in the peptide and binding it to the main chain amino group of the N-terminal. In this manner, a known circularization method may be used without any particular limitation.Pharmaceutical Compositions

[0315] The conjugates (e.g., radiopharmaceuticals) described herein, including e.g., pharmaceutically acceptable salt or solvate thereof, can be administered per se as a pure chemical or as a component of a pharmaceutically acceptable formulation. In some embodiments, a conjugate described herein is combined with a pharmaceutically suitable or acceptable carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Provided herein is a pharmaceutical composition comprising at least one conjugate described herein, or a stereoisomer, pharmaceutically acceptable salt, amide, ester, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.

[0316] In one aspect, the disclosure provides a pharmaceutical composition comprising a herein described conjugate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0317] The conjugates and pharmaceutical compositions of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal,Attorney Docket No. 01277-0089-00PCT-RYZintrathecal and epidural and intranasal, etc.III. METHODS OF TREATMENT

[0318] The present technology also relates to a method for treating a disease or disorder characterized by overexpression or decreased expression of GPC3 by administering the peptide of the present technology to a subject.

[0319] The present technology also relates to a use of the peptide of the present technology for the treatment of a disease or disorder characterized by overexpression or decreased expression of GPC3.

[0320] The present technology also relates to a use of the peptide for manufacturing a pharmaceutical composition for tire treatment of a disease or disorder characterized by overexpression or decreased expression of GPC3.

[0321] The present technology also relates to the peptide of the present technology for use in a method for treating a disease or disorder characterized by overexpression or decreased expression of GPC3.

[0322] The present technology also relates to a kit for use in a method of diagnosing disease or disorder characterized by overexpression or decreased expression of GPC3 by determination of the expression level of GPC3.

[0323] The present technology also relates to a composition for use in a method of diagnosing disease or disorder characterized by overexpression or decreased expression of GPC3.

[0324] The present technology also relates to use of a peptide or a salt thereof for use in a method of diagnosing disease or disorder characterized by overexpression or decreased expression of GPC3.

[0325] Tire present technology also provides methods of treating a disease or condition in a subject in need thereof. In some embodiments, the disease or disorder is characterized by overexpression or decreased expression of GPC3 in diseased tissue. In some embodiments, the disease or disorder is characterized by overexpression of GPC3 in diseased tissue. In some embodiments, the disease or disorder is characterized by decreased expression of GPC3 in diseased tissue. In some embodiments, the methods comprise administering a peptide described herein, a conjugate described herein, or a pharmaceutically acceptable salt or solvate thereof described herein, or a pharmaceutical composition comprising the same, to the subject in need thereof. In some embodiments, provided herein is a method of providing a therapeutic and / or prophylactic benefit to a subject in need thereof comprising administering a peptide, a conjugate, or a pharmaceutical composition described herein.

[0326] In some embodiments, the methods comprise administering to a subject a therapeutically effective amount of a peptide, a conjugate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the peptide, conjugate or pharmaceutically acceptable salt or solvate thereof is administered in a pharmaceutical composition. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor or hematological cancer.

[0327] In one aspect, provided herein is a method of treating cancer by administering a herein described peptide, conjugate or a pharmaceutically acceptable salt or solvate thereof to a subject inAttorney Docket No. 01277-0089-00PCT-RYZneed thereof. According to a further aspect of the disclosure, there is provided a peptide, or a drug conjugate thereof as defined herein, for use in preventing, suppressing or treating a disease or disorder characterized by overexpression or decreased expression of GPC3 in diseased tissue. In some embodiments, the disease or disorder is characterized by overexpression of GPC3 in diseased tissue (such as a tumor). In one embodiment, the GPC3 is mammalian GPC3. In a further embodiment, the mammalian GPC3 is human GPC3.

[0328] In one aspect, provided herein is a method of preventing, suppressing or treating a disease or disorder characterized by overexpression or decreased expression of GPC3 in diseased tissue. In some embodiments, the disease or disorder is characterized by overexpression of GPC3 in diseased tissue (such as a tumor), which comprises administering to a patient in need thereof a peptide or a conjugate described herein. In some embodiments, the disease or disorder characterized by overexpression of GPC3 in diseased tissue is a cancer.

[0329] Non-limiting examples of cancers to be treated by the methods of the present disclosure can include hematological cancer or solid tumor, such as melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer), esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies. In some embodiments, a subject or population of subjects to be treated with a pharmaceutical composition of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a subject or population of subjects to be treated with a pharmaceutical composition of the present disclosure have a hematological cancer. In some embodiments, the subject has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma (“MM”). In some embodiments, a subject or population of subjects to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer, and melanoma. In some embodiments, the cancer is selected from hepatocellular carcinoma, squamous cell carcinoma of the lung, lung adenocarcinoma, germ cell tumors, hepatoblastoma, wilms tumor, malignant rhabdoid tumors, rhabdomyosarcoma, liposarcoma, thyroid cancers, pancreatic cancer, small bowel cancer, small cell neuroendocrine carcinoma (SCNC), castration resistant prostatic adenocarcinoma, ovarian cancer, gastric cancer, esophageal carcinoma and malignant melanoma. In some embodiments, the castration resistant prostatic adenocarcinoma is hormonally treated. In some embodiments, the cancer is neuroendocrine prostate cancer (NEPC).Attorney Docket No. 01277-0089-00PCT-RYZ

[0330] In some embodiments, provided herein are methods and compositions for treating a disease or condition. Exemplary disease or condition includes refractory or recurrent malignancies whose growth may be inhibited using the methods of treatment of the present disclosure. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, hepatocellular cancer, bladder cancer, colorectal cancer, gastric adenocarcinoma, ovarian cancer, melanoma, or advanced cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of tire anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, a cancer to be treated by the methods of the present disclosure include, for example, carcinoma, squamous carcinoma (for example, cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary bladder, tongue, larynx, and gullet), and adenocarcinoma (for example, prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary gland, and ovary). In some embodiments, the cancer is neuroendocrine prostate cancer (NEPC). In some embodiments, a cancer to be treated by the methods of the present disclosure further include sarcomata (for example, myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC). In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is pancreatic cancer. In some embodiments, a cancer to be treated by the methods of the present disclosure is non-small cell lung cancer, ovarian cancer, or bladder cancer. In some embodiments, a cancer to be treated by the methods of the present disclosure is non-small cell lung cancer. In some embodiments, a cancer to be treated by the methods of the present disclosure is bladder cancer. In some embodiments, a cancer to be treated by the methods of the present disclosure is ovarian cancer. In some embodiments, a cancer to be treated by the methods of the present disclosure is hepatocellular carcinoma, squamous cell carcinoma of the lung, lung adenocarcinoma, germ cell tumors, hepatoblastoma, wilms tumor, malignant rhabdoid tumors, rhabdomyosarcoma, liposarcoma, thyroid cancers, pancreatic cancer, small bowel cancer, small cell neuroendocrine carcinoma (SCNC), hormonally treated, castration resistant prostatic adenocarcinoma, ovarian cancer, gastric cancer, esophageal carcinoma, or malignant melanoma.Attorney Docket No. 01277-0089-00PCT-RYZ

[0331] Further examples of cancers (and their benign counterparts) which may be treated include, but are not limited to tumors of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney, lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (for example thyroid follicular carcinoma), adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); hematological malignancies (i.e. leukemias, lymphomas) and premalignant hematological disorders and disorders of borderline malignancy including hematological malignancies and related conditions of lymphoid lineage (for example acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, B-cell lymphomas such as diffuse large B-cell lymphoma, follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukemias, natural killer cell lymphomas, Hodgkin's lymphomas, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and posttransplant lymphoproliferative disorders), and hematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin, for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcoma’s, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (for example astrocytoma’s, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumors and schwannomas); endocrine tumors (for example pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors and medullary carcinoma of the thyroid); ocular and adnexal tumors (for example retinoblastoma); germ cell and trophoblastic tumors (for example teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and pediatric and embryonal tumors (for example medulloblastoma, neuroblastoma, Wilms tumor, and primitive neuroectodermal tumors); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).

[0332] In some embodiments, the cancer is selected from glioblastoma, prostate cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, gladder cancer, colon cancer, esophageal cancer,Attorney Docket No. 01277-0089-00PCT-RYZmultiple myeloma and fibrosarcoma, in some embodiments, the cancer is selected from: breast cancer, lung cancer, gastric cancer, pancreatic cancer, prostate cancer, liver cancer, glioblastoma and angiogenesis. In some embodiments, the cancer is selected from: prostate cancer, lung cancer (such as non-small cell lung carcinomas (NSCLC)), breast cancer (such as triple negative breast cancer), gastric cancer, ovarian cancer, esophageal cancer, multiple myeloma and fibrosarcoma, in some embodiments, the cancer is prostate cancer. In some embodiments, the conjugate is useful for preventing, suppressing or treating solid tumors such as fibrosarcoma’s and breast, and non-small cell lung carcinomas. In some embodiments, the cancer is selected from lung cancer, such as non-small cell lung carcinomas (NSCLC). In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is Herceptin resistant breast cancer. In some embodiments, the subject has failed to respond to Herceptin. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is fibrosarcoma.

[0333] In some embodiments, provided herein are methods for killing a cell comprising contacting the cell with a peptide, a conjugate, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cell expresses GPC3. In some embodiments, the cell over-expresses GPC3. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof binds to a structure on the cell, wherein the structure is an GPC3.

[0334] In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof releases a number of alpha particles by natural radioactive decay. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof releases a number of beta particles, gamma rays, and / or Auger electrons by natural radioactive decay. The conjugate described herein can kill a cell by radiation. In some embodiments, the conjugate kills the cell directly by radiation. In some embodiments, the radiation creates, in the cell, oxidized bases, abasic sites, single -stranded breaks, double-stranded breaks, DNA crosslink, chromosomal rearrangement, or a combination thereof. In some embodiments, the conjugate kills the cell by inducing double-stranded DNA breaks. In some embodiments, the released alpha particles are sufficient to kill the cell. In some embodiments, the released alpha particles are sufficient to stop cell growth. In some embodiments, the conjugate kills the cell indirectly via the production of reactive oxygen species (ROS) such as free hydroxyl radicals. In some embodiments, the cell is a cancer cell. In some embodiments, the method comprises killing a cell with an alpha-particle emitting radionuclide.

[0335] After contacting a cell, the described peptide or conjugate can be internalized by the cell. The internalization can be mediated by cell receptors, cell membrane endocytosis, etc. In some embodiments, the described peptide or conjugate is internalized by a cell through GPC3. In some embodiments, rapid internalization rate into cancer cells accompanied by a slow externalization rate can offer therapeutic benefit.Attorney Docket No. 01277-0089-00PCT-RYZ

[0336] In one aspect, the disclosed peptide, conjugate or a pharmaceutically acceptable salt or solvate thereof is configured to treat cancer by ablating tumor cells. In some embodiments, the peptide, conjugate or a pharmaceutically acceptable salt or solvate thereof does not modulate the biology of the tumor cell and / or the surrounding stroma. In some embodiments, the conjugate or a pharmaceutically acceptable salt or solvate thereof does not modulate immune cells. In some embodiments, the ablating of tumor cells can lead to a downstream immunological cascade.

[0337] In addition to the methods of treatment described above, the conjugates (e.g., radiopharmaceuticals) and compositions described herein can be used to image, and / or as part of a treatment for diseases. Conjugates for imaging applications, e.g., single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can comprise a radionuclide suitable for use as imaging isotopes (e.g,, Dx in Table 10) such as the isotopes in Table 10. Accordingly, a radiopharmaceutical can be administered as a companion diagnostic.

[0338] In one aspect, described herein is a method of treatments that comprises administering a first conjugate and a second conjugate, The first conjugate can be used as companion diagnostics and the second conjugate can be used for therapeutics. In some embodiments, the first conjugate and the second conjugate have the same structure except for the radionuclide. In some embodiments, the first conjugate comprises a gamma particle emitting radionuclide. In some embodiments, the first conjugate comprises a diagnostic radionuclide of Table 10 labeled “Dx.” In some embodiments, the first conjugate comprises a radionuclide selected from Lu-177, In-111, Ga-68, Cu-64, and Zr-89. In some embodiments, the second conjugate comprises an alpha or beta-particle emitting radionuclide. In some embodiments, the second conjugate comprises a therapeutic radionuclide of Table 10 labeled “Tx”. In some embodiments, the second conjugate comprises Ac-225. In some embodiments, the method comprises administering (i) a first conjugate comprising a radionuclide configured for companion diagnostic (such as PET imaging) and (ii) a second conjugate comprising a radionuclide selected from an alpha or beta-particle emitter, wherein the first and the second conjugate have the same structure except for the radionuclide.

[0339] In one aspect, described herein is a method of diagnosing or imaging a cancer in a subject in need thereof, comprising administering to the subject a peptide, a conjugate or a pharmaceutical composition described herein.

[0340] In some embodiments, the subject is 1 to 100 years old. In some embodiments, tire subject is 5 to 10, 5 to 15, 5 to 18, 5 to 25, 5 to 35, 5 to 45, 5 to 55, 5 to 65, 5 to 75, 10 to 15, 10 to 18, 10 to 25, 10 to 35, 10 to 45, 10 to 55, 10 to 65, 10 to 75, 15 to 18, 15 to 25, 15 to 35, 15 to 45, 15 to 55, 15 to 65, 15 to 75, 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to 35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to 65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to 75 years old. In some embodiments, the subject is at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years old. In some embodiments, the subject is at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years old.

[0341] The amount of conjugate (e.g., radiopharmaceutical) described herein or a pharmaceuticallyAttorney Docket No. 01277-0089-00PCT-RYZacceptable salt or stereoisomer thereof and / or pharmaceutical compositions administered can be sufficient to deliver a therapeutically effective dose of tire particular subject. In some embodiments, conjugate dosages can be between about 0.1 pg and about 50 mg per kilogram of body weight. In some embodiments, the dose of the conjugate or a pharmaceutically acceptable salt or stereoisomer thereof described herein for the described methods is about 0.001 mg to about 1000 mg per dose for the subject being treated.

[0342] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the disclosure as defined in the appended claims.

[0343] The present disclosure is further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way.EXAMPLESExample 1: Synthesis of the Conjugates

[0344] Unless otherwise stated in the present specification, the following abbreviations are used according to the following meanings:Abbreviation MeaningAlloc allyloxycarbonylaq. aqueousBiotin-OSu biotin N-hydroxysuccinimide ester (CAS 35013-72-0)Boc tert-butyl oxy carbonylClAcOH chloroacetic acidClAcOSu N-succinimidyl 2 -chloroacetate (CAS 27243-15-8)DCM dichloromethane (CAS 75-09-2)DIC N, NT -diisopropylcarbodiimide (CAS 693-13-0)DIPEA, DIEA N, N-diisopropylethylamine (CAS 7087-68-5)DMEM Dulbecco's Modified Eagle MediumDMF N, N-dimethylformamide (CAS 68-12-2)DODT 2,2'-(ethylenedioxy)diethanethiol (CAS 14970-87-7)N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (CAS 25952-53- EDCI-HC18)EDTA ethylened iami n etetraacetic acidEMEM Eagle's minimal essential mediumeq equivalentEt ethylEt3N, TEA triethylamine (CAS 121-44-8)FBS fetal bovine serumFmoc 9-fluorenylmethoxycarbonylhr hourl-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide HATUhexafluorophosphate (CAS 148893-10-1)HOSu N-hydroxysuccinimide (CAS 6066-82-6)Attorney Docket No. 01277-0089-00PCT-RYZiPrOH, IPA isopropanolM molarmin minutesNHS N-hydroxysuccinimide (CAS 6066-82-6)NMP N-methylpyrrolidone (CAS 872-50-4)Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3)PG protecting groupPh phenylRP reverse phaserpm rotations per minutert room temperatureSAPE Streptavidin, R-Phycoerythrin conjugateSPPS solid phase peptide synthesisSu succinimidylSulfoCy5- sulfo Cyanine5 (CAS 2791287-13-1)SulfoCy5-OSu, (CAS 146368-14-1)SulfoCy5-NHS see SulfoCy5-OSutert tertiaryTFA trifluoroacetic acid (CAS 76-05-1)TIS triisopropylsilane (CAS 6485-79-6)tr retention timeTrt trityl(7-azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate PyAOP(CAS 156311-83-0)MeCN acetonitrileAcOH acetic acidEt2O diethyl etherAA amino acidMe methylHFIP 1,1,1,3,3,3-hexafluoro-2-propanol (CAS 920-66-1)PhSiH3 phenylsilane (CAS 694-53-1)tBu tertiary butylDMSO dimethylsulfoxideMpe 3 -Methyl-pent-3 -ylExample 1A. Analytical Conditions

[0345] Solid phase peptide synthesis (SPPS) was performed in a standard manual reaction vessel under nitrogen. Sieber Resin was purchased from Sunresin New Materials Co. (China). Fmoc protected amino acids were purchased from GL Biochem (China). HBTU and HATU were purchased from Highfine Biotech Co. (China). Piperidine was purchased from Damao Chemical Reagent Factory (China). Tire peptides and their derivatives were purified on a Gilson GX-281 preparative HPLC system using reverse-phase C18 columns (Gemini, 5 pm, 110 A + luna, 10 pm, 100 A) at 30CC. HPLC solvents consisted of H2O containing 0.075% trifluoroacetic acid (mobile phase A) andAttorney Docket No. 01277-0089-00PCT-RYZacetonitrile (mobile phase B).

[0346] High performance liquid chromatography (HPLC) analyses were performed on an Agilent 1260 series equipped with a binary pump G7112A, micro vacuum degasser, standard autosampler ALS G7129A, thermostatted column compartment TCC G7116A, variable wavelength detector VWD G7114A, and data were analyzed by OpenLab CDS 2.2 network workstation software from Agilent Technologies. HPLC solvents consisted of H2O containing 0.1% trifluoroacetic acid (mobile phase A) and acetonitrile containing 0.075% trifluoroacetic acid (mobile phase B). Conditions: a Phenomenex Gemini-NX C-l 8 (5 pm, 110 A, 4.6 x 250 mm) column -was used with a flow rate of 1.0 mL / min.

[0347] LC-MS analyses were carried out on an Agilent 1200 series coupled to an Agilent MSD G6125C, equipped with a binary pump G7112A, micro vacuum degasser, standard autosampler ALS G7129A, thermostatted column compartment TCC G7116A, variable wavelength detector VWD G7114A, and data were analyzed by OpenLab CDS 2.3 standalone workstation software from Agilent Technologies. HPLC solvents consisted ofH2O containing 0.1% trifluoroacetic acid (mobile phase A) and acetonitrile containing 0.075% tri fluoroacetic acid (mobile phase B). Conditions: a Waters Xbridge C-18 (3.5 pm, 3.1 x 30mm) column was used with a flow rate of 1.2 mL / min.Example 2A: Synthesis of Lu-C-72 (SEQ ID NO: 616)Attorney Docket No. 01277-0089-00PCT-RYZFmoc— HN —; Sieber ResinFmoc deprotectionH2NFmoc-N-Me-Cys(Trt)-OH, HBTU, DIEA; DMFFmoc deprotectionFmoc-N-Me-Cys(Trt)-NSPPS HATU / HBTU; piperidineB i oc O i tBu T irt tBu t iBu T i rt. H.H2N -MeK -MeHseMe D-MeQ-F4COO-|— I — Y-MeNal27N G~3Py6Ph— MeC— NBrAc; DICBoc OtBu Trt tBu tBu TrtI I l l i I H AABrAc-MeK— MeHseMe-D-MeQ~F4COO---|— I— Y -MeNal27N-G-3Py6Ph— MeC— N~L J1Scheme 1. Synthesis of peptidyl -resin 1

[0348] To the swollen Sieber Resin (0.3 mmol, 0.44mmol / g, 1.00 equiv) was removed via 20 min agitation with 20% piperidine in DMF followed by filtration and washing. Then the resin was added Fmoc-N-Me-Cys(Trt)-OH (0.54 g, 0.9 mmol) HBTU (0.32g, 0.85 mmol) and DIEA (0.23g, 1.8 mmol) in dry DMF. The mixture was agitated for 30min under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 m ). The Fmoc protecting group was removed via 30 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0349] Subsequent amino acids were coupled using Fmoc-protected amino acid (3.00 equiv), HATU / HBTU (2.85 equiv) and DIEA (6,00 equiv) in dry DMF, shaking for 30 min. Pre -activation of any amino acid was not performed prior to coupling. Between amino acid couplings, the Fmoc protecting group was removed via 30 min agitation with 20% piperidine in DMF followed by filtration and washing. Success of Fmoc removal steps and amino acid couplings were monitored qualitatively using a ninhydrin test.

[0350] At the last step, to the swollen Sieber resin were added BrAc (0.25 g, 1.80 mmol), and DIGAttorney Docket No. 01277-0089-00PCT-RYZ(0.23 g, 1.80 mmol) in DMF (5 mL). The mixture was agitated for 10 min under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (8 mL).Boc OtBu Trt tBu tBu Tri BrAc-MeK— MeHseMe-D— MeQ— F4COO— I— I — Y-MeNal27N-G— 3Py6Ph— MeC— N1 TFA, TIS, H2O, 3-MPA u BrAc-MeK— MeHseMe-D— MeQ-F4COO-|— I — Y-MeNal27N-G— 3Py6Ph— MeC— NH21a CS2GO3 VAc— MeK— MeHseMe-D— MeQ— F4COO— |— I — Y-MeNal27N-G— 3Py6Ph— MeC~ NH21b DOTA-OSu, DEA VAttorney Docket No. 01277-0089-00PCT-RYZLu-C-72Scheme 2. Synthesis of the cyclic peptide and Lu complex (SEQ ID NOS 616, 617, 618, 258 and 2 8, respectively, in order of appearance).

[0351] After the resin was washed three times with MeOII and dried under vacuum, a cocktail of trifluoroacetic acid / H2O / triisopropylsilane / 3-mercaptopropionic acid (90:2.5:2.5:5.0) was added. The resulting mixture was stirred for 1.5 h at room temperature. Cold isopropyl ether was added, lire precipitated crude linear peptide- la was collected through filtration and dried under vacuum,

[0352] Cyclization of peptide-la: To a solution of crude la (480 mg) in water (120 mL) and MeCN (60 mL) were added Cs2CO3 (3.0 eq). The resulting mixture was stirred at room temperature for 0.5 hour, lire pH of the solution was then adjusted to 6-7 using 1.0 N HQ. After lyophilization, the crude was purified by preparative HPLC to afford peptide- lb (SEQ ID NO: 72) (123 mg, 85% purity) as a white solid.

[0353] To a solution of peptide- lb (123 mg) in DMF (6 mL) were added DOTA-OSu (1.5 eq), DIEA (3 eq). The resulting mixture was heated to 40°C and stirred at 40°C 1 hour, the crude was purified by preparative HPLC to afford C-72 (65 mg, 94.21% purity).

[0354] Lu3+ complexation: To a solution of C-72 (40mg, 94.21% purity) in ...

Claims

Attorney Docket No. 01277-0089-00PCT-RYZCLAIMSWe claim:

1. A conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising:(a) a peptide of Formula I:1^•*11 / X<:<j X4Xg.•■ X:',_.... Xs;' ""-x / Formula I,wherein:R is -CH2-CO-; and(i) Xi is MeLys, MeLysAc, MeAla, MeGlu, MeGln, or CrpG, wherein the N-terminal nitrogen of Xi is attached to the C(O) of R; andX2 is Melle, MeGln, MeLys, MellseMe, MeLysCOpipzaa, or MeGlu; andX3 is Asp, MeAsp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andX4 is MeGln, MeLys, MeAspapCOpipzaa, MeGlu, or CrpG; andX5is F4COO, MeF4C00, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andX6 is TMe, altMe, Ile, or Leu; andX7 is TMe, He, Vai, Leu, Gcpe, or Eva; andX8is Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; andX9is MeNal27N, MeF3Me4C, MeF34dOMe, or MeW7N; andX10 is Gly, MeGly, D-Ala, D-Ser, or D-Pro; andXu is 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4pipl Ac, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; andX12 is MeCys or Cys, wherein sulfur of the Xn side chain is covalently attached to R,„ O^NH2o2N N H2and carboxylic acid of X12 is replaced with -CfOjNIL orH; and wherein Xi is MeGlu or CrpG; or X2 is MeLys; or X3 is MeAsp, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or X4 is MeGlu, or CrpG; or Xs is MeF4C00, 4Py, 3Py6NH2,Attorney Docket No. 01277-0089-00PCT-RYZ3Py6COO, F4(SO3H), or (PyrrCOO)A; or Xe is alTMe or Leu; or X7 is TMe, Vai, Leu, Gcpe, or Eva; or Xs is Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or X9is MeF3Me4C, MeF34dOMe, or MeW7N; or X]0is MeGly, D-Ala, D-Ser, or D-Pro; orXn is 3Py6Pyrazoll, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; orX^is Cys; or(ii) Xi to X12 have a sequence from Table 1, 2, 3, 4, 9A, or 20A; and(b) a metal chelator covalently attached to the peptide.

2. The conjugate or pharmaceutically acceptable salt thereof of claim 1, comprising(a) a peptide of Formula I, wherein:R is -CH2-CO-; and(i) Xi is MeLys, MeLysAc, Me Ala, MeGlu, MeGln, or CrpG. wherein the N-terminal nitrogen of Xi is attached to the C(O) of R; andX2is Melle, MeGln, MeLys, MeHseMe, MeLysCOpipzaa, or MeGlu; andX3is Asp, MeAsp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andX4 is MeGln, MeLys, MeAspapCOpipzaa, MeGlu, or CrpG; andX5is F4COO, MeF4C00, Y, 4Py, 3Py6NH2, 3P 6COO, F4(SO3H), or (PyrrCOO)A; andX6is TMe, altMe, He, or Leu; andX7is TMe, He, Vai, Leu, Gcpe, or Eva; andX8is Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py 6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; andX9is MeNal27N, MeF3Me4C, MeF34dOMe, or MeW7N; andX10 is Gly, MeGly, D-Ala, D-Ser, or D-Pro; andXu is 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4pip lAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; andX12 is MeCys or Cys, wherein sulfur of the Xn side chain is covalently attached to R,oO^NH2NNH2and carboxylic acid of X12 is replaced with -C(O)XH2orH; and wherein Xi is MeGlu or CrpG; or X2is MeLys; or X3is MeAsp, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or X4is MeGlu, or CrpG; or X5is MeF4C00, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; or Xe is alTMe or Leu; or X? is TMe, Vai, Leu, Gcpe, or Eva; or Xs is Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or X9is MeF3Me4C, MeF34dOMe, or MeW7N; or X]0is MeGly, D-Ala, D-Ser, or D-Attorney Docket No. 01277-0089-00PCT-RYZPro; or Xu is 3Py6Pyrazoll, 3Py6O4pipIMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; or Xi2is Cys; or(ii) X; to X12 have a sequence from Table 1, 2, 3, 4, or 9A; and(b) a metal chelator covalently attached to the peptide.

3. A conjugate or pharmaceutically acceptable salt thereof, the conjugate comprising:(a) a peptide of Formula II:Formula IIwherein:R* is -CH₂-S-CH₂-CO-;each Z is independently selected from H and Me; andO^NHaAN N HzQis -NH2or H; and(i) A; is the side chain of Lys, Lys Ac, Ala, Glu, Gin, or CrpG; andA2is the side chain of He, Gin, Lys, HseMe, LysCOpipzaa, or Glu; andA3is the side chain of Asp, Hgn, Ser, Ihr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andA4 is the side chain of Gin, Lys, AspapCOpipzaa, Glu, or CrpG; andAs is the side chain of F4COO, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andAf, is the side chain of TMe, altMe, He, or Leu; andA? is the side chain of Tme, He, Vai, Leu, Gcpe, or Eva; andAttorney Docket No. 01277-0089-00PCT-RYZAg is the side chain of Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; andA9 is the side chain of Nal27N, F3Me4C, F34dOMe, or W7N; andAjo is the side chain of Gly, D-Ala, D-Ser, or D-Pro; andAn is the side chain of 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C;and wherein Ai is the side chain of Glu or CrpG; or A2is the side chain of Lys; or A3is the side chain of Asp, Ser, Thr, Ala, or Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or A4 is the side chain of Glu or CrpG; or As is the side chain of F4COO, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; or As is the side chain of alTMe or Leu; or A7 is tire side chain of Tme, Vai, Leu, Gcpe, or Eva; or Asis the side chain of Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or A9is the side chain of F3Me4C, MeF34dOMe, or MeW7N; or A10 is the side chain of Gly, D-Ala, D-Ser, or D-Pro; or An is the side chain of 3Py6PyrazoIl, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; or(ii) Ai to An correspond to the side chains of X;to Xn of a sequence from Table 1, 2, 3, 4, 9A, or 20A; and(b) a metal chelator covalently attached to the peptide.

4. The conjugate or pharmaceutically acceptable salt thereof of claim 3, comprising:(a) a peptide of Formula II, wherein:R* is -CH2-S-CH2-CO-;each Z is independently selected from H and Me; andO.^NH2AN N HzQis -NFL or H; and(i) Ai is the side chain of Lys, LysAc, Ala, Glu, Gin, or CrpG; andA2is the side chain of He, Gin, Lys, HseMe, LysCOpipzaa, or Glu; and A3is the side chain of Asp, Hgn, Ser, Thr, Ala, Lys, Glu, Asn, diMeDap, Hva, or (S)Mor(2CO); andA4is the side chain of Gin, Lys, AspapCOpipzaa, Glu, or CrpG; and Asis the side chain of F4COO, Y, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; andAs is the side chain of TMe, altMe, He, or Leu; andA? is the side chain of Tme, He, Vai, Leu, Gcpe, or Eva; andAttorney Docket No. 01277-0089-00PCT-RYZAg is the side chain of Tyr, Cha, F30H, F4aao, F4COO, F4aa, Yae, YaeCOpipzaa, F4F, F4U, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; andA9 is the side chain of Nal27N, F3Me4C, F34dOMe, or W7N; andAjo is the side chain of Gly, D-Ala, D-Ser, or D-Pro; andAn is the side chain of 3Py6Ph, 3Py6Pyrazoll, F41Me4Pyz, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C;and wherein Ai is the side chain of Glu or CrpG; or A2is the side chain of Lys; or A3is the side chain of Asp, Ser, Thr, Ala, or Lys, Glu, Asn, diMeDap, (S)Mor(2CO), or Hva; or A4 is the side chain of Glu or CrpG; or As is the side chain of F4COO, 4Py, 3Py6NH2, 3Py6COO, F4(SO3H), or (PyrrCOO)A; or As is the side chain of alTMe or Leu; or A7 is tire side chain of Tme, Vai, Leu, Gcpe, or Eva; or Asis the side chain of Cha, F30H, F4F, Aph, 3Py6NH2, 4Py, F4(C0NMe0H), F4C0NHMe, F4CONMe2, or (PyrrCOO)A; or A9is the side chain of F3Me4C, MeF34dOMe, or MeW7N; or A10 is the side chain of Gly, D-Ala, D-Ser, or D-Pro; or An is the side chain of 3Py6PyrazoIl, 3Py6O4piplMs, 3Py6O4piplAc, 3Py6O4thp, F43Py5H, F44Pdo, 3Py63Py5, 3Py63Py, 3Py61ap4, F41apPyz, F42Py, F44Py, or Bph4C; or(ii) Ai to An correspond to the side chains of X;to Xn of a sequence from Table 1, 2, 3, 4, or 9A; and(b) a metal chelator covalently attached to the peptide.

5. The conjugate or pharmaceutically acceptable salt thereof of claim 1, wherein Xj to X)2of the peptide of Formula (I) have a sequence from Table 1, 2, 3, 4, 9A, or 20A.

6. The conjugate or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein Xi to Xi2of the peptide of Formula (I) have a sequence from Table 1, 2, 3, 4, or 9A,7. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 1, 2, and 6, wherein Xi to Xi2of the peptide of Formula (1) have the sequence of SEQ ID NO: 226, 520, or 521.

8. A conjugate or pharmaceutically acceptable salt thereof, wherein the conjugate is a conjugate from Table 5, 6, 7, 8, 9B, or 20B.

9. A conjugate or pharmaceutically acceptable salt thereof, wherein the conjugate is a conjugate from Table 5, 6, 7, 8, or 9B.

10. The conjugate or pharmaceutically acceptable salt thereof of claim 7, selected from C-226- DOTA, C-226-NOTA, C-520, and C-521.

11. The conj ugate of pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein the metal chelator is covalently attached to the side chain of the first amino acid of the peptide (Xi, A;), the side chain of the second amino acid of the peptide (X2, A2), the side chain of the third amino acid of the peptide (X3, A3), the side chain of the fourth amino acid of the peptideAttorney Docket No. 01277-0089-00PCT-RYZ(X4, A4), the side chain of the eighth amino acid of the peptide (Xs, As), or to the C-terminus of the C-terminal amino acid of the peptide (X12, Q, when Q is -NH2); or wherein the peptide comprises a thirteenth ammo acid and the metal chelator is covalently attached to the side chain of the thirteenth amino acid (X, Q, when Q is D-Lys).

12. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-7 and 11, wherein the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-D0TA, NH2-D0TA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn- oxo-DO3A, NOTA, NODA-GA, NH2-N0DA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn- NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-N0DA, PCTA, p-NH2-Bn- PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACR0PA-NCS, H1-MACR0PA, H2- MACR0PA-NH2, H4-OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA.

13. The conjugate or pharmaceutically acceptable salt thereof of claim 12, wherein the metalAttorney Docket No. 01277-0089-00PCT-RYZDOTA).

14. The conjugate or pharmaceutically acceptable salt thereof of claim 13, wherein the metal chelator is:O 0(DOTA).

15. The conjugate or pharmaceutically acceptable salt thereof of claim 12, wherein the metal oO I H / \"NA / O iichelator is ° (NOTA).

16. lire conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-7 and 11-15, further comprising a linker that covalently connects the peptide to the metal chelator.

17. The conjugate or pharmaceutically acceptable salt thereof of claim 16, wherein the linker comprises 3 to 10 intervening non-hydrogen, organic atoms between the metal chelator and the peptide.

18. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-7 and 11-15, wherein the peptide is directly attached to the metal chelator.

19. Tire conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-18, wherein the conjugate comprises a radionuclide bound to the metal chelator.Attorney Docket No. 01277-0089-00PCT-RYZ20. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-10 and 19, wherein the conjugate has the following structure (SEQ ID NO: 591):OH wherein X^is a radionuclide.

21. The conj ugate or pharmaceutically acceptable salt thereof of any one of claims 1-10 and 19, wherein the conjugate has the following structure (SEQ ID NO: 592):Attorney Docket No. 01277-0089-00PCT-RYZwherein XMis a radionuclide.

22. The conjugate or pharmaceutically acceptable salt thereof of any one of claims l-10 and 19, wherein the conjugate has the following structure (SEQ ID NO: 614):Attorney Docket No. 01277-0089-00PCT-RYZwherein XMis a radionuclide.

23. The conjugate or pharmaceutically acceptable salt thereof of any one of claims l-10 and 19, wherein the conjugate has the following structure (SEQ ID NO: 615):Attorney Docket No. 01277-0089-00PCT-RYZOH wherein X^is a radionuclide.

24. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 19-23, wherein the radionuclide is an alpha particle-emitting radionuclide.

25. The conjugate or pharmaceutically acceptable salt thereof of claim 24, wherein the alpha particle-emitting radionuclide is Ac -225, Bi-213, Bi-209, 115-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213.

26. The conjugate or pharmaceutically acceptable salt thereof of claim 24 or 25, wherein the alpha particle-emitting radionuclide is Ac-225.

27. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 19-23, wherein the radionuclide is a beta particle-emitting radionuclide.

28. The conjugate or pharmaceutically acceptable salt thereof claim 27, wherein the beta particle¬ emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or Tb-161.

29. The conjugate or pharmaceutically acceptable salt thereof of claim 27 or 28, wherein the beta particle-emitting radionuclide is Lu-177.

30. The conjugate or pharmaceutically acceptable salt thereof of any one of claims 19-23, wherein the radionuclide is a positron-emitting radionuclide.Attorney Docket No. 01277-0089-00PCT-RYZ31. The conjugate or pharmaceutically acceptable salt thereof of claim 30, wherein the positronemitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152.

32. The conjugate or pharmaceutically acceptable salt thereof of claim 30 or 31, wherein the positron-emitting radionuclide is Ga-68.

33. The conjugate or pharmaceutically acceptable salt thereof, of any one of claims 1-32, wherein the peptide is not any of SEQ ID Nos: 1-72.

34. The conjugate or pharmaceutically acceptable salt thereof, of any one of claims 1-33, wherein the conjugate is not a conjugate of Table B.

35. A pharmaceutical composition comprising the conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-34, and a pharmaceutically acceptable excipient or carrier.

36. A method of treating a disease or disorder characterized by overexpression of glypican 3 (GPC3) in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the conjugate or pharmaceutically acceptable salt thereof of any one of claims 19-34 or the pharmaceutical composition of claim 35.

37. A method of treating a disease or disorder characterized by overexpression of GPC3 in a subject in need of treatment, the method comprising:administering to the subject a first conjugate or pharmaceutically acceptable salt thereof comprising a first radionuclide; andadministering to the subject a therapeutically effective amount of a second conjugate or pharmaceutically acceptable salt thereof comprising a second radionuclide, wherein:the first conjugate or pharmaceutically acceptable salt thereof is the conjugate or pharmaceutically acceptable sale thereof of any one of claims 19-34; andthe second conjugate or pharmaceutically acceptable salt thereof is the conjugate or pharmaceutically acceptable salt thereof of any one of claims 19-34; and wherein the first radionuclide and second radionuclide are different radionuclides.

38. The method of claim 37, wherein the first radionuclide is a diagnostic radionuclide, and the second radionuclide is a therapeutic radionuclide.

39. A method of diagnosing a disease or disorder characterized by overexpression of GPC3 in a subject in need thereof, comprising administering to the subject the conjugate or pharmaceutically acceptable salt thereof of any one of claims 19-34, or the pharmaceutical composition of claim 35; and imaging the subject, thereby determining expression level of GPC3 in the subject, wherein the radionuclide is suitable for use as an imaging isotope.

40. The method of any one of claims 36-39, wherein the disease or disorder is cancer.

41. The method of claim 40, wherein the cancer is hepatocellular carcinoma, squamous cell carcinoma of the lung, lung adenocarcinoma, germ cell tumors, hepatoblastoma, wilms tumor, malignant rhabdoid tumors, rhabdomyosarcoma, liposarcoma, thyroid cancers, pancreaticAttorney Docket No. 01277-0089-00PCT-RYZcancer, small bowel cancer, small cell neuroendocrine carcinoma (SCNC), hormonally treated, castration resistant prostatic adenocarcinoma, ovarian cancer, gastric cancer, esophageal carcinoma, or malignant melanoma.

42. A kit, tester, or composition for determining expression level of GPC3 in a sample, wherein the kit, tester, or composition comprises a conjugate or pharmaceutically acceptable salt thereof of any one of claims 1-34, or the pharmaceutical composition of claim 35.

43. The kit, tester, or composition of claim 42, adapted for use in a method of diagnosing a disease or disorder characterized by an overexpression or a decreased expression of GPC3.

44. The kit, tester, or composition of claim 42 or 43, wherein the sample is from a subject suspected of having a disease or disorder characterized by an overexpression or a decreased expression of GPC3,

Images