Composition for treating cancer, comprising interleukins and calcium compounds

Abstract

This specification provides polypeptides containing therapeutic agents targeted for delivery to organs or tissues, and their uses.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 505,026, filed May 30, 2023, which is hereby incorporated by reference in its entirety.

[0002] Sequence Listing This application includes a sequence listing, which is submitted in XML format together with this specification and is hereby incorporated by reference in its entirety. The XML copy created on May 29, 2024, is named 50222-712_601.xml and is 122,650 bytes in size. Technical Background

[0003] Cytokines are effective in activating the immune system and can be used as immunomodulators to stimulate the immune system for the treatment of cancer. However, systemic administration of cytokines induces serious side effects, which limits their wider use.

Summary of the Invention

[0004] In various embodiments, immunomodulator compositions and systems for the treatment of cancer are provided herein. In various embodiments, the immunomodulators are localized to the target cancer and reduce or eliminate systemic side effects associated with the systemic delivery of the immunomodulator that are not localized. Exemplary compositions and systems include variant interleukins, variant human leukocyte antigen (HLA) receptors (also called major histocompatibility complex receptors), tumor antigen peptides, and combinations thereof. Various embodiments include particles to which the variant interleukin and / or variable HLA are tethered. The variant HLA may be combined with a tumor antigen peptide. The compositions and systems may be delivered systemically.

[0005] This specification provides a method for activating an immune response and / or treating cancer in a subject requiring treatment for cancer, the method comprising the step of delivering an immunomodulatory polypeptide comprising an interleukin and particles comprising a calcium compound to the subject. In some embodiments, the immunomodulatory polypeptide comprises a binding peptide that binds to the calcium compound of the particles. In some embodiments, the binding peptide comprises a sequence that is at least 80% identical to one of SEQ ID NOs: 12-14 and 1-11. In some embodiments, the immunomodulatory polypeptide comprises a protease cleavage site located between the interleukin and the binding peptide, the protease cleavage site being cleaved by proteases of T cells and / or cancer cells. In some embodiments, the protease cleavage site includes (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of sequence numbers 47-50, 106-108, 124-125, 127-128, and 112-113.In some embodiments, the immunomodulatory polypeptide includes a linker located between the interleukin and the binding peptide, the linker having (i) a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (i) SEQ ID NO: 42, and / or at least identical to SEQ ID NO: 111. (ii) sequences that are identical by 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, respectively. For sequences that are 9% identical, sequence number 43, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or for sequences that are 99% identical, sequence number 104, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, Sequences that are 95%, 96%, 97%, 98%, or 99% identical, and / or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 105, or (iii) containing one or more of sequence numbers 36-52, 101-113, and 124-125. In some embodiments, the interleukin includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 16, 15, and 94-100. In some embodiments, the interleukin includes IL2, IL12, IL21, IL15, IL7, IL24, or IL28.In some embodiments, the immunomodulatory polypeptide is localized to a target site in the subject, the immunomodulatory polypeptide does not result in systemic activation of the immune response, delivery to the subject results in fewer side effects than delivery of a particle-free immunomodulatory polypeptide to the subject, and / or the method results in cancer-specific immune activation. In some embodiments, the method includes the step of administering an immune checkpoint inhibitor to the subject. In some embodiments, the immune checkpoint inhibitor includes an anti-PD1 antibody. In some embodiments, the cancer is malignant melanoma, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, uterine cancer, bladder cancer, thyroid cancer, ovarian cancer, or breast cancer. In some embodiments, delivery is by intratumoral (IT) injection, guided injection into lymph nodes, or tumor embolization via subcutaneous, intramuscular, or intravenous catheter. In some embodiments, delivery is performed during surgery, colonoscopy, or endoscopy. In some embodiments, the particles are about 1 micron to about 100 microns in size. In some embodiments, the calcium compound comprises beta-tricalcium phosphate.

[0006] This specification provides compositions comprising calcium compound particles and peptide fusion proteins containing a binding peptide linked to an immunomodulatory polypeptide, wherein the binding peptide binds to the calcium compound, linking the peptide fusion protein to the calcium compound particles, and optionally, the immunomodulatory polypeptide comprises interleukin (IL), interferon α (IFNα), interferon α-2 (IFNα2), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), or interleukin 4 (IL4). In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the immunomodulatory polypeptide comprises an interleukin, which comprises IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the immunomodulatory polypeptide comprises an interleukin, which comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs.In some embodiments, the composition includes a linker position between the binding peptide and the immunomodulatory polypeptide, wherein the linker is (i) identical to (i) at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the sequence to SEQ ID NO: 42 and / or at least 80% identical to SEQ ID NO: 111 (ii) Sequences that are identical by 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. For identical sequences, sequence number 43, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or for 99% identical sequences, sequence number 105, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , sequences that are 95%, 96%, 97%, 98%, or 99% identical, and / or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104, or (iii) containing one or more of sequence numbers 36-52, 101-113, and 124-125. In some embodiments, the composition comprises a protease cleavage site located between the binding peptide and the immunomodulatory polypeptide, the protease cleavage site comprising (i) a furin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase (MMP) cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113.In some embodiments, the particles are about 1 micron to about 100 microns in size. In some embodiments, the calcium compound comprises β-tricalcium phosphate.

[0007] This specification includes the following formulas: Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, or Formula 12: TA-BP (Equation 1), TA-L-BP (Equation 2), BP-TA (Equation 3), BP-L-TA (Equation 4), TA1-L1-BP-L2-TA2 (Equation 5), TA1-BP-TA2 (formula 6), TA1-L1-BP-TA2 (formula 7), TA1-BP-L1-TA2 (formula 8), BP1-L1-TA-L2-BP2 (Equation 9), BP1-TA-BP2 (formula 10), BP1-L1-TA-BP2 (Equation 11), BP1-TA-L1-BP2 (Equation 12) A fusion protein is provided, In the formula, each TA, TA1, and TA2 is independently a therapeutic agent, each L, L1, and L2 is independently a linker, and each BP, BP1, and BP2 is independently a binding peptide. Each therapeutic agent independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of the following: immunomodulators, anticancer agents, antigen peptides, or sequence numbers 15-23, 53, 58-100, and 122. Each bound peptide independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14, and Each linker independently includes (i) a furin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of sequence numbers 36-52, 101-113, 127-128, and 124-125.

[0008] This specification provides polypeptides containing sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 24, 114, 25-35, 54-57, 126, and 115-121.

[0009] This specification includes (i) a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), and (ii) SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLDLQMILNGINN A polypeptide is provided containing an interleukin-2 sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT.

[0010] This specification includes (i) a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13 (AAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), and (ii) SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLDLQM A polypeptide comprising interleukin-2 is provided, containing at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequences to ILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT.

[0011] This specification includes polypeptides, (i) A sequence identical to sequence number 16 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT) in terms of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, (ii) (a) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 1 (ILAETTHHRPWS), (b) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 2(STADTSHHRPST), (c) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 3 (VGADSTHHRPVT), (d) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4 (LIADSTHHSPWT), (e) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 5 (AAESTSKKRPFS), (f) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 7 (VIGESTHHRPWS), (g) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 10 (ILAESTHHKPWT), (h) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 8 (IIGESSHHKPFT), (i) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 9 (GLGDTTHHRPWG), (j) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 6(LLADTTHHRPWT), (k) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 11, (l) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 12, (m) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 13, (n) A sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 14, or Combinations containing two or more sequences from (o)(a)~(n) and A subsystem including this is provided.

[0012] In some embodiments of the polypeptides herein, the polypeptide comprises a linker located between (i) and (ii), wherein the linker is (i) a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (i) SEQ ID NO: 42, and / or SEQ ID NO: 111 (ii) Sequences that are identical by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, respectively. For sequences that are 99% identical, sequence number 43, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or for sequences that are 99% identical, sequence number 104, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , sequences that are 95%, 96%, 97%, 98%, or 99% identical, and / or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 105, or (iii) containing one or more of sequence numbers 36-52, 101-113, and 124-125.

[0013] In some embodiments of the polypeptides herein, the polypeptide comprises a protease cleavage site located between (i) and (ii), the protease cleavage site comprising (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113. In some embodiments, the cleavable linker comprises SEQ ID NOs: 106 (RKKR) or SEQ ID NOs: 113 (RKKRSTDEVDGAPPLGL).

[0014] This specification provides a polypeptide comprising (i) a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to Sequence ID No. 13 (AAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), (ii) a first interleukin-2, and (iii) a second interleukin-2, wherein the first interleukin-2 and the second Each of the two interleukin-2s independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 16 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT). In some embodiments, (i) is located between (ii) the first interleukin-2 and (iii) the second interleukin-2. In some embodiments, (i) and (ii) are linked via a first linker, and (i) and (iii) are linked via a second linker. In some embodiments, the first linker includes one or more of sequence numbers 36-52, 124-125, and 101-113, and the second linker includes one or more of sequence numbers 36-52, 124-125, and 101-113.In some embodiments, the first linker comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more of SEQ ID NOs: 103, 109, and 104, and the second linker comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more of SEQ ID NOs: 103, 109, and 104. In some embodiments, the first linker comprises (i) a furin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of one or more of SEQ ID NOs: 47 - 50, 106 - 108, 124 - 125, 127 - 128, and 112 - 113, and the second linker comprises (i) a furin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of one or more of SEQ ID NOs: 47 - 50, 106 - 108, 124 - 125, 127 - 128, and 112 - 113. In some embodiments, the first linker comprises a furin cleavage site and the second linker comprises a furin cleavage site.

[0015] The present specification provides polypeptides comprising a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13 (AAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), or SEQ ID NO: 14 (LIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWT).

[0016] The present specification provides nucleic acids encoding the compositions, fusion proteins, or polypeptides of the present specification. The present specification provides vectors comprising the nucleic acids of the present specification.

[0017] The present specification provides kits comprising particles containing the compositions, fusion proteins, or polypeptides of the present specification, and calcium compounds.

[0018] This specification provides a method for treating a subject requiring treatment, the method comprising the step of delivering to the subject a composition, fusion protein, polypeptide, or kit of this specification. The method may include the step of administering an immune checkpoint inhibitor to the subject. The immune checkpoint inhibitor may include an anti-PD1 antibody. The treatment method may include the step of treating cancer in the subject, the cancer being malignant melanoma, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, uterine cancer, bladder cancer, thyroid cancer, ovarian cancer, or breast cancer. The treatment method may include the step of activating an immune response in the subject. Delivery may be by intratumor (IT) injection, lymph node induction injection, or tumor embolization via subcutaneous, intramuscular, or intravenous catheter. Delivery may be performed during surgery, colonoscopy, or endoscopy. [Brief explanation of the drawing]

[0019] [Figure 1] The diagram shows the treatment of cancer patients by injecting TCP (tricalcium phosphate) particles linked with mutant IL-2 peptide and mutant HLA-A peptide, where the mutant HLA-A peptide is bound to a neoantigen peptide (NA123; SEQ ID NO: 123 NGFEQARDC). [Figure 2] This document describes the engineering process for designing carrier particles and variant IL-2 peptides, attaching the IL-2 peptides to the carriers, and preparing constructs for delivery as a treatment. [Figure 3] This paper describes a process for designing carrier particles, a mutant IL-2 peptide, and a mutant HLA fusion peptide, attaching the mutant IL-2 peptide and mutant HLA fusion peptide to the carrier, combining them with a neoantigen peptide to generate neoantigen-peptide loaded particles, and delivering the loaded particles as a treatment. [Figure 4]The results of protein refolding experiments for ILX-1, ILX-2, ILX-3, ILX-4, ILX-5, ILX-6, ILX-7, and ILX-8, labeled as lanes 1-8, are shown. [Figure 5] The tests for the solubility of ILX-1, ILX-4, ILX-5, and ILX-7 in PBS, performed by passing SDS-PAGE gel through the dialysate after centrifugation, are shown. [Figure 6] This shows the response of CTLL-2 cells to IL2 activity in response to increased doses of ILX-1, ILX-4, ILX-5, and ILX-7 compared to a control. CTLL-2 cell proliferation was evaluated using AlamarBlue reagent. [Figure 7] This assay demonstrates the ability of ILX-1, ILX-4, ILX-5, and ILX-7 to bind to bTCP (β-tricalcium phosphate) particles. [Figure 8] This assay demonstrates the ability of ILX-5 and ILX-7 to bind to hydroxyapatite and bTCP particles of different sizes. [Figure 9] This shows the expression levels of plasmids encoding ILX-5, ILX-51, and ILX-71 derived from transformed E. coli THX01. [Figure 10] The results of solubility tests for ILX-51 and ILX-71 at various pH levels are shown. [Figure 11] The results of solubility tests for ILX-51 and ILX-71 at various urea concentrations are shown. [Figure 12] The results of the solubility test of ILX-71 in 6M urea solution versus 6M GuHCl solution are shown. [Figure 13] This shows the results of an evaluation of the ILX-71's refolding capability. [Figure 14] This shows the expression level of ILX-52 induced by E. coli. [Figure 15]The results of solubilization tests of inclusion bodies for ILX-52 at various urea concentrations are shown. [Figure 16A] This shows the quantification of the amount of solubilized ILX-52 recovered from the inclusion body using 8M urea buffer. [Figure 16B] The calibration curve used to calculate the mass of the recovered ILX-52 is shown. [Figure 17] The results of testing the refolding ability of ILX-52 after exposure to urea buffer at various concentrations and to 8M urea in 0.8M ArgHCl buffer are shown. [Figure 18] The results of dialysis of ILX-52, which was refolded in dialysis buffer after oxidation with glutathione disulfide, are shown. [Figure 19] The response of CTLL-2 cells to IL2 activity in response to increasing doses of ILX-5 refolded and dialyzed with various urea concentrations is shown compared to a control. CTLL-2 cell proliferation was evaluated using AlamarBlue reagent. [Figure 20] This study demonstrates the response of CTLL-2 cells to IL2 activity in response to increasing doses of refolded ILX-5, which is either free, bound to hydroxyapatite particles, or bound to two different sizes of bTCP particles. CTLL-2 cell proliferation was evaluated using AlamarBlue reagent. [Figure 21] This shows the expression of multiple HLA constructs (HLA-t, HLA-at, HLA-b) in recombinant E. coli. [Figure 22] This shows the solubilization of HLA-t from inclusion bodies in urea buffer at various concentrations. [Figure 23] This shows the expression of HLA-bat constructs in recombinant E. coli. [Figure 24A] This shows the quantification of the amount of solubilized HLA-bat recovered from the inclusion body using 8M urea buffer. [Figure 24B]The calibration curve used to calculate the mass of the recovered HLA-bats is shown. [Figure 25] The results of HLA-bat refolding in the presence or absence of the TLTSCNTSV peptide after overnight dialysis with PBS are shown. [Figure 26] This shows expression of the α and β chains of DR1 MHC-II transformed E. coli THXH01, but does not show significant expression of the DR1α chain. [Figure 27A] This report presents the results of administering ILX-52 and β-TCP particles (ILX-52 / bTCP) in combination with anti-PD-1 antibody (1x or 5x anti-PD-1 antibody: ILX-52 / bTCP 1x + anti-PD1 or ILX-52 / bTCP + anti-PD1 5x, respectively) to a mouse murine melanoma model, compared to administering β-TCP particles (bTCP) or bTCP and anti-PD-1 antibody. The results show that treatment with ILX-52 / bTCP and anti-PD-1 antibody improves tumor volume reduction compared to treatment with bTCP or bTCP and anti-PD-1 antibody. [Figure 27B] This report presents the results of administering ILX-52 and β-TCP particles (ILX-52 / bTCP) in combination with anti-PD-1 antibody (1x or 5x anti-PD-1 antibody: ILX-52 / bTCP 1x + anti-PD1 or ILX-52 / bTCP + anti-PD1 5x, respectively) to a mouse model of malignant melanoma, compared to administering β-TCP particles (bTCP) or bTCP and anti-PD-1 antibody. The results show that mice treated with ILX-52 / bTCP and 5x anti-PD-1 antibody survived longer than the control group. [Figure 28A]The results of administering ILX-52 (ILX-52) with βTCP combined with an anti-PD-1 antibody or ILX-74 (ILX-74) with bTCP, compared to treatment with bTCP alone, in a mouse model of malignant melanoma, in terms of tumor volume. The results show improvement in tumor volume reduction with treatment with bTCP and ILX-52 with an anti-PD-1 antibody compared to treatment with bTCP alone. The results show improvement in tumor volume reduction with treatment with bTCP and ILX-74 with an anti-PD-1 antibody compared to treatment with bTCP alone. [Figure 28B] The results of administering ILX-52 (ILX-52) with βTCP combined with an anti-PD-1 antibody or ILX-74 (ILX-74) with bTCP, compared to treatment with bTCP alone, in a mouse model of malignant melanoma, in terms of survival probability. The results show that mice treated with ILX-52 and the anti-PD-1 antibody along with bTCP survived longer than mice treated with bTCP alone. The results also show that mice treated with ILX-74 and the anti-PD-1 antibody along with bTCP survived longer than mice treated with bTCP alone. Detailed description of the invention

[0020] In various embodiments, methods for activating an immune response in subjects requiring activation of an immune response are provided herein, the methods comprising the step of delivering an immunomodulatory polypeptide linked to a delivery particle to the subject, the immunomodulatory polypeptide comprising a conjugating peptide that links the immunomodulatory polypeptide to the delivery particle. In various embodiments, methods for treating cancer in subjects requiring treatment of cancer are provided herein, the methods comprising the step of delivering an immunomodulatory polypeptide linked to a delivery particle to the subject, the immunomodulatory polypeptide comprising a conjugating peptide that links the immunomodulatory polypeptide to the delivery particle. In some embodiments, the immunomodulatory polypeptide is localized to a target site in the subject. In some embodiments, the immunomodulatory polypeptide linked to the delivery particle does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of an immunomodulatory polypeptide not linked to a delivery particle. The methods may further include the step of delivering an antigen (tumor antigen) associated with the cancer of the subject to the subject. The methods may include the step of administering an immune checkpoint inhibitor to the subject. A non-limiting example is an anti-PD-1 antibody.

[0021] Furthermore, this specification also provides a method for activating an immune response in a subject that requires activation of an immune response to treat cancer, the method comprising the step of delivering an anticancer agent conjugated to particles containing a calcium compound to the subject. Furthermore, this specification also provides a method for treating cancer in a subject that requires treatment of cancer, the method comprising the step of delivering an anticancer agent conjugated to particles containing a calcium compound to the subject. In some embodiments, the method localizes the anticancer agent to a target site in the subject. In some embodiments, the anticancer agent does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of an anticancer agent that is not conjugated to delivery particles. In some embodiments, the method results in cancer-specific immune activation. In some embodiments, the anticancer agent comprises a conjugating peptide that binds to the calcium compound of the particles. In some embodiments, the anticancer agent comprises a protease cleavage site, which is optionally cleaved by T cell proteases and / or cancer cell proteases in the subject. The method may further include a step of delivering an antigen (tumor antigen) associated with the cancer of the subject. The method may also include a step of administering an immune checkpoint inhibitor to the subject. An anti-PD-1 antibody is a non-limiting example.

[0022] Furthermore, this specification also provides compositions and systems for modulating immune responses in subjects. Compositions and systems may be used in methods described herein. Exemplary compositions include peptide fusion proteins. In various embodiments, peptide fusion proteins are provided that include a binding peptide linked to an immunomodulatory polypeptide, the binding peptide interacting with a delivery particle to ligate the peptide fusion to the delivery particle. In some embodiments, the binding peptide binds to the delivery particle. In some embodiments, the delivery particle includes a calcium compound, and the binding peptide binds to the calcium compound. Non-limiting examples of immunomodulatory peptides include interleukin (IL), interferon-α (IFNα), interferon-α-2 (IFNα2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-4 (IL4).

[0023] In various embodiments of this specification, the immunomodulatory polypeptide comprises an interleukin. In some embodiments, the interleukin comprises IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs.

[0024] In various embodiments of this specification, the immunomodulatory polypeptide comprises a human leukocyte antigen (HLA) receptor. In some embodiments, the HLA receptor comprises the α chain and / or the β chain of the HLA receptor. In some embodiments, the HLA receptor is a class I or class II HLA receptor. In some embodiments, the HLA receptor comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 17-22, 53, or 122.

[0025] Various embodiments of this specification provide compositions, systems, and kits comprising immunomodulatory polypeptides and / or anticancer agents, as well as delivery particles. In some embodiments, the delivery particles include calcium compounds. Non-limiting examples of calcium compounds include calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, hydroxyapatite, metal oxides, or passedivated materials.

[0026] Various embodiments of this specification provide compositions, systems, and kits comprising immunomodulatory polypeptides and / or anticancer agents, optionally delivery particles, and tumor antigen peptides. In some embodiments, the tumor antigen peptides are specific to the cancer of the subject.

[0027] Furthermore, this specification also provides nucleic acids that encode polypeptides and peptide fusion proteins described herein. Vectors containing nucleic acids are further provided.

[0028] Binding peptides In one embodiment, a binding peptide is provided herein. The binding peptide may bind to a particle or a component thereof. In some embodiments, the binding peptide binds to a calcium compound of the particle. Non-limiting examples of binding peptides are shown in Table 1.

[0029] In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the bound peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7.In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the bound peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14.

[0030] In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6.In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14.

[0031] [Table 1]

[0032] Therapeutic drugs In one embodiment, therapeutic agents are provided herein. Non-limiting examples of therapeutic agents include immunomodulators, anticancer agents, and antigenic peptides. Sequences of non-limiting examples of peptide therapeutic agents are shown in Table 2.

[0033] Various embodiments include immunomodulators as therapeutic agents. In some embodiments, the immunomodulator is an immunomodulatory peptide. Non-limiting examples of immunomodulatory peptides include interleukins (IL), interferon-α (IFNα), interferon-α-2 (IFNα2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-4 (IL4). In exemplary embodiments, the immunomodulatory peptide includes an interleukin. For example, the interleukins are IL-2, IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In exemplary embodiments, the immunomodulatory peptide includes a human leukocyte antigen (HLA) receptor. The HLA receptor may be a class I receptor, e.g., HLA-A, HLA-B, or HLA-C. The HLA receptor may be a class II receptor. HLA receptors may have α and β chains, which can reside on a single or two separate peptide molecules.

[0034] Various embodiments include anticancer agents as therapeutic agents. In some embodiments, the anticancer agent includes interleukin (IL), interferon-α (IFNα), interferon-α-2 (IFNα2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), or interleukin-4 (IL4). In exemplary embodiments, the anticancer agent includes interleukin. For example, the interleukin is IL-2, IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In exemplary embodiments, the anticancer agent includes human leukocyte antigen (HLA) receptors. The HLA receptor may be a class I receptor, e.g., HLA-A, HLA-B, or HLA-C. The HLA receptor may be a class II receptor. The HLA receptor may have α and β chains, which may reside on a single or two separate peptide molecules. If the HLA receptor contains α and β chains, the peptide may also include a connecting peptide located between the α and β chains. Non-limiting examples of connecting peptides include the linker peptides in Table 4 and peptides that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the peptides in Table 4.

[0035] Various embodiments include an antigenic peptide as a therapeutic agent. The antigenic peptide may be present on cancer cells. The antigenic peptide may be at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the antigen of the cancer cell. The antigen may contain any one of the sequences in Table 5. The antigenic peptide may be at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequences in Table 5. The antigen may contain any one of sequence numbers 58-93. The antigen peptide may be at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one sequence of sequence numbers 58-93.

[0036] In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 15. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 17. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 18. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 19. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 20.In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 21. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 22. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 23. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 122. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 53. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 94.In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 95. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 96. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 97. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 99. In some embodiments, therapeutic agents such as immunomodulators and / or anticancer agents include a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 100.

[0037] In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 15. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 17. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 18. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 19. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 20.In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 21. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 22. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 23. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 122. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 53. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 94.In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 95. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 96. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 97. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 99. In some embodiments, the polypeptides, fusion proteins, compositions, systems, or kits herein include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 100.

[0038] [Table 2-1]

[0039] [Table 2-2]

[0040] [Table 3]

[0041] Polypeptides, fusion proteins, metabolites, and compositions In one embodiment, polypeptides comprising a binding peptide (e.g., a peptide that can be bound to a carrier material) and a therapeutic agent are provided herein. In certain embodiments, the polypeptide is a fusion protein. Furthermore, compositions comprising the polypeptide and fusion protein herein are provided. Non-limiting examples of binding peptides include those in Table 1 and peptides having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the peptides in Table 1. Non-limiting examples include immunomodulators, anticancer agents, antigenic peptides, peptides from Table 2, and peptides having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the peptides from Table 2. In some embodiments, the binding peptide and the therapeutic agent are linked via a linker. Non-limiting examples of linkers include peptides from Table 4, and peptides having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the peptides from Table 4. If present, the linker may contain a protease cleavage site. Non-limiting examples of peptides and fusion proteins are shown in Table 3. Each of the sequences in Table 3 may contain an N-terminal methionine for recombinant protein expression. Non-limiting configurations of fusion proteins provided herein include: TA-BP (Equation 1), TA-L-BP (Equation 2), BP-TA (Equation 3), BP-L-TA (Equation 4), TA1-L1-BP-L2-TA2 (Equation 5), TA1-BP-TA2 (formula 6), TA1-L1-BP-TA2 (formula 7), TA1-BP-L1-TA2 (formula 8), BP1-L1-TA-L2-BP2 (Equation 9), BP1-TA-BP2 (formula 10), BP1-L1-TA-BP2 (Equation 11), and BP1-TA-L1-BP2 (Equation 12) is included, In the formulas, each TA is a therapeutic agent, each L is a linker, and each BP is a binding peptide. The linker may include any linker as defined herein and may include protease cleavage sites. When the formula includes TA1 and TA2, TA1 and TA2 may be the same or they may be different. When the formula includes L1 and L2, L1 and L2 may be the same or they may be different. When the formula includes BP1 and BP2, BP1 and BP2 may be the same or they may be different. In some formulas, BP represents one or more binding peptides, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 binding peptides, which may include the same or two or more different binding peptides. In some cases, TA includes immunomodulators. In some cases, TA includes anticancer agents. In some cases, the TA comprises a first TA and a second TA, optionally linked via a linking peptide or linker.

[0042] In some embodiments, each therapeutic agent (e.g., TA, TA1, and TA2) independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 15-23, 53, 58-100, and 122. In some embodiments, the therapeutic agent contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16.

[0043] In some embodiments, each linker (e.g., L, L1, and L2) independently includes (i) a furin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, (v) one or more of SEQ ID NOs: 36-52, 124-125, 127-128, and 101-113, or (vi) any combination of (i)-(v) above. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 42, and / or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 111. In some embodiments, the linker has sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence 43, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence 103. The sequence includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence 104, and / or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence 105.In some embodiments, the linker has sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence 103, and at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 8 Sequences that are 8%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, and / or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109. In some embodiments, the linker includes one or more of sequence numbers 36-52, 124-125, and 101-113. In some embodiments, the linker includes protease cleavage sites, e.g., furin cleavage sites, caspase cleavage sites, matrix metalloproteinase cleavage sites, cathepsin cleavage sites, or combinations of cleavage sites. In some embodiments, the linker includes a furin cleavage site.

[0044] In some embodiments, each binding peptide (e.g., BP, BP1, and BP2) is independently a binding peptide, and each binding peptide independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1 to 14. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the conjugated peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14.

[0045] In some embodiments, the formula of the fusion protein is not limiting and may therefore include one or more additional sequences. For example, a fusion protein having formula 1 is provided, where the additional peptide is located between TA and BP, before TA, after BP, or in any combination thereof.

[0046] In some embodiments of the fusion proteins, polypeptides, or compositions herein, the fusion proteins, polypeptides, or compositions include protease cleavage sites, and protease cleavage produces metabolites. In some embodiments, metabolites are provided herein that contain sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 115. In some embodiments, metabolites are provided herein that contain sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 116. In some embodiments, metabolites are provided herein that contain sequences identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 117. In some embodiments, metabolites are provided herein that contain sequences identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 118. In some embodiments, metabolites are provided herein that contain sequences identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 119. In some embodiments, metabolites are provided herein that contain sequences identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 120.In some embodiments, metabolites are provided herein that contain sequences identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 121. In some embodiments, metabolites are provided herein that contain sequences identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 126.

[0047] [Table 4-1]

[0048] [Table 4-2]

[0049] [Table 4-3]

[0050] In some embodiments, the polypeptides and fusion proteins described herein comprise two or more binding peptides (e.g., BP, BP1, BP2, etc.). In some embodiments, the two or more binding peptides are about 2, 3, 4, 5, 6, 7, 8, 9, or 10 binding peptides. In some embodiments, each binding peptide is about 5 to about 15 amino acids, about 10 to about 15 amino acids, or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids. In some embodiments, the total number of amino acids in two or more bound peptides is about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, or about 30 to about 80 amino acids.

[0051] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0052] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0053] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. The polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0054] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0055] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0056] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 20. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0057] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 21. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0058] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 22. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0059] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 122. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to at least one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0060] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 53. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0061] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 94. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0062] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 95. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0063] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 96. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0064] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 97. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0065] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0066] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 99. In some embodiments, the first binding peptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0067] In some embodiments, polypeptides or fusion proteins comprising a first binding peptide (e.g., BP, BP1, BP2, etc.) and a first therapeutic agent (e.g., TA, TA1, TA2, etc.) are provided herein, wherein the first therapeutic agent comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 100. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 6. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 7. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 9. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12.In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13. In some embodiments, the first binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14. A polypeptide or fusion protein may contain two or more additional binding peptides, one or more of which are optionally selected from sequences from Table 1, or sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more sequences from Table 1. A polypeptide or fusion protein may comprise one or more linkers (e.g., L, L1, L2, etc.) that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more linkers in Table 4. Compositions, systems, and kits comprising polypeptides and particles of the fusion protein are further provided. The binding peptide may bind to the particles. For example, the particles may contain a calcium compound, and the binding peptide may bind to the calcium compound.

[0068] In some embodiments, a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS) is used, and SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP Polypeptides or fusion proteins are provided herein that comprise interleukin-2 having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT). In some embodiments, the bound peptide and interleukin-2 are linked via a linker (e.g., L, L1, L2, etc.). In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 42 (GGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGG). In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109.In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 36. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109.In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104. In some embodiments, the linker includes sequences that are identical to sequence number 109 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and sequences that are identical to sequence number 104 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 50 (RKKRSTDEVDGAPPLGLWAVGGGG). In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 112. In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 113. In some embodiments, the linker includes a Fuline cleavage site. In some embodiments, the linker includes a caspase cleavage site. In some embodiments, the linker includes a matrix metalloproteinase (MMP) cleavage site.In some embodiments, the linker includes a cathepsin cleavage site. In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47. In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 48. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 49. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 107. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 108. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 127.In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 128. In some embodiments, the polypeptide comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 24 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGRKKRSTDEVDGAPPLGLWAVGGGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT). In some embodiments, the polypeptide includes SEQ ID NO: 24.In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13 (AAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), a first interleukin-2, and a second interleukin-2. Each of the first interleukin-2 and the second interleukin-2 independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT). In some embodiments, the binding peptide is located between the first interleukin-2 and the second interleukin-2. In some embodiments, the binding peptide and the first interleukin-2 are linked via a first linker (e.g., L, L1, L2, etc.). In some embodiments, the first linker is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 124. The sequence is included. In some embodiments, the first linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103. In some embodiments, the first linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 36. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 111.In some embodiments, the first linker includes an array that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104. In some embodiments, the first linker includes a Fulin cleavage site. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106.In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37.In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104. In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 36. In some embodiments, the first linker is identical to sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109, and is identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 110. In some embodiments, the first linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37, and a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104.In some embodiments, the first linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 36. In some embodiments, the first linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 37, and a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 110. In some embodiments, the binding peptide and the second interleukin-2 are linked via a second linker (e.g., L, L1, L2, etc.). In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 125. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103. In some embodiments, the second linker includes an array that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to array 109.In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, or 86% identical to sequence number 36. , includes sequences that are 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 110. In some embodiments, the second linker includes a Fulin cleavage site. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47.In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 37, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 109, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104.In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 36. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 47, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 110. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104. In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 36.In some embodiments, the second linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 106, and sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 110. In some embodiments, the polypeptide is sequence number 114 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGSGGHMGSGGRKKRSTEAAAKEAAAKEAAAKGGGSGGGSGGAAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGG The polypeptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to GSGGHMGSGGEAAAKEAAAKEAAAKRKKRSTGGGSGGGSGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT). In some embodiments, the polypeptide contains SEQ ID NO: 114.

[0069] In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), a first interleukin-2, and a second interleukin-2, wherein the first interleukin-2 is... Each of the interleukin-2 and the second interleukin-2 independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT). In some embodiments, the binding peptide is located between the first interleukin-2 and the second interleukin-2. In some embodiments, the binding peptide and the first interleukin-2 are linked via a first linker (e.g., L, L1, L2, etc.). In some embodiments, the first linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 46 or 101. In some embodiments, the first linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 50 (RKKRSTDEVDGAPPLGLWAVGGGG).In some embodiments, the binding peptide and the second interleukin-2 are linked via a second linker (e.g., L, L1, L2, etc.). In some embodiments, the second linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 42 (GGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGG). In some embodiments, the second linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 50 (RKKRSTDEVDGAPPLGLWAVGGGG). In some embodiments, the polypeptide is sequence number 25(APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLTRKKRSTDEVDGAPPLGLWAVGGGGSGGGSGGEAAAKEAAAKEAAAKGGGSGGHMGSGGAAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGGGS The sequence contains elements that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to GGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGRKKRSTDEVDGAPPLGLWAVGGGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT).In some embodiments, the polypeptide includes SEQ ID NO: 25.

[0070] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, and 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11, and an interleukin-2 containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 15. In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 26 (LLADTTHHRPWTVIGESTHHRPWSIIGESSHHKPFTGLGDTTHHRPWGILAESTHHKPWTASGAGGSEGGGSEGGTSGATGAGTSTSGGGASTGGGTGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT).

[0071] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 11, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to Sequence ID No. 27 (LLADTTHHRPWTVIGESTHHRPWSIIGESSHHKPFTGLGDTTHHRPWGILAESTHHKPWTASGAGGSGGGGSGGGTSGATGAGTSTSGGGASTGGGTGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT).

[0072] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 11, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 28 (LLADTTHHRPWTVIGESTHHRPWSIIGESSHHKPFTGLGDTTHHRPWGILAESTHHKPWTASGAGGSKGGGSKGGTSGATGAGTSTSGGGASTGGGTGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT).

[0073] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 12, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 29 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGGGSGGHKGGGGKEAAAKEAAAKGGGGSGGGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT).

[0074] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 12, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 30 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT).

[0075] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 11, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, Sequence ID 31(APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLTASGAGGSEGGGSEGGTSGATGAGTSTSGGGASTGGGTGLLADTTHHRPWTVIGESTHHRPWSIIGESSHHKPFTGLGDTTHHRPWGILAESTHHKPWTASGAGGSEGGGSEGGTSGATGAGTSTSGGGA Polypeptides or fusion proteins are provided herein that contain a conjugated peptide having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to STGGGTGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT.

[0076] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 12, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, Sequence ID 32 (APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLTGGGSGGHKGGGGKEAAAKEAAAKEAAAKGGGGSGGGGILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSASGAGGSKGGGSKGGTSGATGAGTSTSGGGAST Polypeptides or fusion proteins are provided herein that contain a conjugated peptide having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (GGGTGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT).

[0077] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 11, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15. In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 12, and an interleukin-2 containing a sequence identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 94%, 95%, 96%, 97%, 98%, or 99% of SEQ ID NO: 15.In some embodiments, Sequence ID 33(LLADTTHHRPWTVIGESTHHRPWSIIGESSHHKPFTGLGDTTHHRPWGILAESTHHKPWTGGGSGGHKGGGGKEAAAKEAAAKEAAAKGGGGSGGGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSII Polypeptides or fusion proteins are provided herein that contain a conjugated peptide having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to STLTGGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS).

[0078] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12, and an interleukin-2 containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16. In some embodiments, polypeptides or fusion proteins are provided herein that include a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 34 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT).

[0079] In some embodiments, polypeptides or fusion proteins are provided herein that comprise a conjugated peptide (e.g., BP, BP1, BP2, etc.) containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12, and an interleukin-2 containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16. In some embodiments, Sequence ID 35(APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLTGGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGAAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFSGGGSGGHMGSGGEAAAKEAAAKEAA Polypeptides or fusion proteins are provided herein that contain a conjugated peptide having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to AKGGGSGGGSGGAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT).

[0080] In some embodiments, a polypeptide or fusion peptide containing a conjugated peptide containing a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS) is included. Synthetic protein, and (i) SEQ ID NO: 17 (GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQRTDAPKTHMTH (ii) Sequence ID 18 (IQRTPKIQVYSRHP) is identical to (HAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE) by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and (ii) Sequence ID 18 (IQRTPKIQVYSRHP) HLA receptors are provided herein that include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (AENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM). In some embodiments, (i) and (ii) are linked via a continuous peptide.In some embodiments, the linked peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 45 (GGSGGGGSGGGGGSGGGGGSGGGGGSGGGGGSGGGGGSGGGGSGGGGGSGGGGG). In some embodiments, the linked peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 52 (GSSSSGSSSSGSSSS). In some embodiments, the HLA receptor is sequence number 19(GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQR The sequence contains an array that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to YTCHVQHEGLPKPLTLRWEGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGSGGGGSGGSGGGSGGGMIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM).In some embodiments, the HLA receptor is sequence number 53 (IQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDMGSSSSGSSSSGSSSSGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYD The sequence contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to GKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWE). In some embodiments, the binding peptide and the HLA receptor are linked via a linker. In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 43 or 102.In some embodiments, the linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 50 (RKKRSTDEVDGAPPLGLWAVGGGG). In some embodiments, the polypeptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, or 99% identical to sequence number 54 (GSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQRTDAPKTHMTHHAVSDHEATLRCW ALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWEGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSGGMIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM The polypeptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to GGGSGGHMGSGGEAAAKEAAAKEAAAKGGGSGGGSGGILAETTHHRPWSSTADTSHHRPSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS). In some embodiments, the polypeptide contains SEQ ID NO: 54.In some embodiments, the polypeptide is sequence number 55 (IQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDMGSSSSGSSSSGSSSSGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETL The polypeptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to QRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWERKKRSTDEVDGAPPLGLWAVGGGGEAAAKEAAAKEAAAKGGGSGGGSGGLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWT). In some embodiments, the polypeptide contains SEQ ID NO: 55.

[0081] In some embodiments, a polypeptide or fusion protein comprising a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 14 (LIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWT), and (i) SEQ ID NO: 22 (GDTRPRFLWQLKFECHFFNGTERVRLLERSIYNQEESVRF HLA receptors comprising sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to DSDVGEYRAVTELGRPDAEYWNSQKDLLEQRRAAVDTYCRHNYGVGESFTVQRRVEPKVTVYPSKTQPLQHHNLLVCSVSGFYPGSIEVRWFRNGQEEKAGVVSTGLIQNGDWTFQTLVMLETVPRSGEVYTCQVEHPSVTSPLTVEWRA) ​​are provided herein. In some embodiments, the binding peptide and the HLA receptor are linked via a linker. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 43 or 102. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 50 (RKKRSTDEVDGAPPLGLWAVGGGG).In some embodiments, the polypeptide is sequence number 56 (GDTRPRFLWQLKFECHFFNGTERVRLLERSIYNQEESVRFDSDVGEYRAVTELGRPDAEYWNSQKDLLEQRRAAVDTYCRHNYGVGESFTVQRRVEPKVTVYPSKTQPLQHHNLLVCSVSGFYPGSIEVRWFRNGQEEKAGVVSTGLIQNGDWTFQTLVMLETVPRSGEVYTCQVEHPSVTSPLTVEWRARKKR The polypeptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to STDEVDGAPPLGLWAVGGGGEAAAKEAAAKEAAAKGGGSGGGSGGLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWT. In some embodiments, the polypeptide contains SEQ ID NO: 56. In some embodiments, the polypeptide is sequence number 57 (IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPETTERKK The polypeptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to RSTDEVDGAPPLGLWAVGGGGEAAAKEAAAKEAAAKGGGSGGGSGGLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWTLIADSTHHSPWWT). In some embodiments, the polypeptide contains SEQ ID NO: 57.

[0082] Linker In some embodiments, the polypeptides, fusion proteins, and compositions herein include a linker. The linker may be located between the binding peptide and the therapeutic agent. The linker may be located between a first therapeutic agent and a second therapeutic agent.

[0083] In some embodiments, the linker comprises a flexible linker in which at least about four amino acids do not have a regular secondary structure. In some embodiments, the regular secondary structure comprises any helical structure (e.g., α-helix, 310-helix, π-helix), β-turn, omega-loop, and / or β-sheet. In some embodiments, the flexible linker comprises at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% glycine, serine, or glycine and serine residues. In some embodiments, the linker comprises 1, 2, 3, 4, or 5 sequences having GGGS (SEQ ID NO: 36). In some embodiments, the linker comprises 1, 2, 3, 4, or 5 sequences having GGSGG (SEQ ID NO: 44). In some embodiments, the linker comprises 1, 2, 3, 4, or 5 sequences having SEQ ID NO: 45. In some embodiments, the linker includes sequences 1, 2, 3, 4, or 5 having sequence number 52. In some embodiments, the linker includes sequences 1, 2, 3, 4, or 5 having sequence number 104. In some embodiments, the linker includes sequences 1, 2, 3, 4, or 5 having sequence number 110. In some embodiments, the linker includes sequences 1, 2, 3, 4, or 5 having sequence number 111.

[0084] In some embodiments, the linker includes a rigid linker in which at least seven amino acids form a helical structure. In some embodiments, the rigid linker includes 1, 2, 3, 4, or 5 sequences having (EAAAK)n (Sequence ID 37), where n is 1 to 5. In some cases, n is 1. In some cases, n is 2. In some cases, n is 3. In some cases, n is 4. In some cases, n is 5. In some cases, the linker includes Sequence ID 109. In some embodiments, the linker includes both movable and rigid linkers.

[0085] In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 38. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 39. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 40. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 41. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 42. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 43. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 46.In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 51. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 101. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 102. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 103. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 105. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 124. In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 125.

[0086] In some embodiments, the linker includes protease cleavage sites. These cleavage sites may be cleaved by proteases present in the tumor microenvironment. They may also be cleaved by proteases of immune cells. Exemplary cleavage sites include those cleaved by furin, caspase, cathepsin, and matrix metalloproteinases (MMPs). Examples of furin cleavage sites include SEQ ID NOs. 47 and 106. Exemplary caspase cleavage sites include SEQ ID NOs. 48 and 107. Exemplary MMP cleavage sites include SEQ ID NOs. 49 and 108. Exemplary cathepsin cleavage sites include SEQ ID NOs. 127 and 128. In some embodiments, the linker includes one, two, three, four, or five protease cleavage sites. Non-limiting examples of cleavage sites include those having SEQ ID NOs. 47-50, and peptides that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to peptides having SEQ ID NOs. Non-limiting examples of cleavage sites include those having SEQ ID NOs. 106-108, and peptides that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to peptides having SEQ ID NOs. Non-limiting examples of cleavage sites include those having SEQ ID NOs. 112-113, and peptides that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to peptides having SEQ ID NOs. Non-limiting examples of cleavage sites include those having SEQ ID NOs. 124-125, and peptides that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to peptides having SEQ ID NOs.Non-limiting examples of cleavage sites include those having SEQ ID NOs. 127-128, and peptides that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the peptides having SEQ ID NOs. 127-128.

[0087] In some embodiments, the linker includes a sequence of about 5 to about 50 amino acids. For example, about 5 to about 45, about 5 to about 40, about 5 to about 35, about 5 to about 30, about 5 to about 20, about 5 to about 15, about 10 to about 50, about 10 to about 45, about 10 to about 40, about 10 to about 35, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 50, about 15 to about 45, about 15 to about 40, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 15 to about 20, about 20 to about 50, about 20 to about 45, about 20 to about A sequence of 40, approximately 20-35, approximately 20-30, approximately 20-25, approximately 25-50, approximately 25-45, approximately 25-40, approximately 25-35, approximately 25-30, approximately 30-50, approximately 30-45, approximately 30-40, approximately 30-35, approximately 35-50, approximately 35-45, approximately 35-40, approximately 40-50, approximately 40-45, approximately 45-50, approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids.

[0088] [Table 5]

[0089] Nucleic acid / vector Furthermore, this specification also provides nucleic acids that encode any of the peptides, polypeptides, fusion proteins, and compositions described herein.

[0090] Furthermore, this specification also provides vectors comprising any of the nucleic acids provided herein. A vector may refer to a polynucleotide capable of inducing the expression of a recombinant peptide in a host cell. In some embodiments, the vector further comprises a promoter and / or enhancer operably ligated to any of the nucleic acids described herein.

[0091] Production method Furthermore, this specification provides methods for producing peptides, polypeptides, fusion proteins, and compositions, the methods comprising the steps of introducing a nucleic acid sequence encoding a peptide into cells to produce recombinant cells, and culturing the recombinant cells under conditions sufficient for peptide expression. In some embodiments, the introduction step includes introducing an expression vector containing a nucleic acid sequence encoding a peptide into the cells.

[0092] This specification provides methods for isolating peptides from cells, such as ion-exchange chromatography, affinity chromatography, and / or size exclusion chromatography.

[0093] Carrier material In one embodiment, a carrier material (sometimes referred to as a carrier particle, delivery particle, delivery material, or particle) that can be combined with the polypeptides, conjugated peptides, therapeutic agents, fusion proteins, and / or other compositions described herein is provided herein. In some embodiments, the conjugated peptide is bound to the carrier material. In some embodiments, the carrier material is a material to which the conjugated peptide of this specification can be bound.

[0094] In some embodiments, the carrier material comprises a calcium compound. Non-limiting examples of calcium compounds include calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, hydroxyapatite, metal oxides, or materials passivated with oxygen or nitrogen. In some embodiments, the calcium compound comprises calcium phosphate. In some embodiments, the calcium compound comprises tricalcium phosphate. In some embodiments, the calcium compound comprises β-tricalcium phosphate.

[0095] In certain non-limiting embodiments, β-tricalcium phosphate may be alternatively referred to as β-tricalcium phosphate, β-TCP, b-TCP, bTCP, β-TCP, and / or β-TCP.

[0096] In some embodiments, the carrier material consists of particles having a diameter of approximately 1 micron to approximately 150 microns. In some embodiments, the carrier material consists of particles having a diameter of approximately 5 microns to approximately 50 microns. In some embodiments, the carrier material consists of particles having a diameter of approximately 40 microns. In some embodiments, the carrier material is a particle having a diameter of at least 1 micron, at least 5 microns, at least 10 microns, at least 15 microns, at least 20 microns, at least 25 microns, at least 30 microns, at least 35 microns, at least 40 microns, at least 45 microns, at least 50 microns, at least 55 microns, at least 60 microns, at least 65 microns, at least 70 microns, at least 75 microns, at least 80 microns, at least 85 microns, at least 90 microns, at least 95 microns, at least 100 microns, at least 105 microns, at least 110 microns, at least 115 microns, at least 120 microns, at least 125 microns, at least 130 microns, at least 135 microns, at least 140 microns, at least 145 microns, at least 150 microns, at least 160 microns, at least 170 microns, at least 180 microns, at least 190 microns, at least 200 microns, or larger.

[0097] In some embodiments, the carrier material is particles having a diameter of 1 micron or less, 5 microns or less, 10 microns or less, 15 microns or less, 20 microns or less, 25 microns or less, 30 microns or less, 35 microns or less, 40 microns or less, 45 microns or less, 50 microns or less, 55 microns or less, 60 microns or less, 65 microns or less, 70 microns or less, 75 microns or less, 80 microns or less, 85 microns or less, 90 microns or less, 95 microns or less, 100 microns or less, 105 microns or less, 110 microns or less, 115 microns or less, 120 microns or less, 125 microns or less, 130 microns or less, 135 microns or less, 140 microns or less, 145 microns or less, 150 microns or less, 160 microns or less, 170 microns or less, 180 microns or less, 190 microns or less, 200 microns or less, or larger. In some embodiments, the carrier material may be particles having a diameter within the range defined by any of the aforementioned values.

[0098] Compositions and kits This specification also provides compositions (e.g., pharmaceutical compositions) comprising any of the conjugated peptides, polypeptides, therapeutic agents, and / or fusion proteins described herein. In some examples, the compositions and kits further comprise carrier materials provided herein. In some embodiments, the compositions are conjugated to the carrier material.

[0099] In some cases, the composition is placed in a sterile vial or a pre-loaded syringe.

[0100] In some cases, the composition is formulated for different routes of administration. Non-limiting examples include intratumor (IT) injection, lymph node induction injection, and tumor embolization via subcutaneous, intramuscular, or intravenous catheter.

[0101] Furthermore, this specification also provides kits comprising any of the compositions, conjugated peptides, polypeptides, therapeutic agents, and / or fusion proteins described herein. In some embodiments, the kit includes instructions for carrying out any of the methods described herein. In some examples, the kit includes at least one dose of any of the compositions described herein. In some embodiments, the kit includes a delivery system (e.g., a syringe) for administering any of the compositions described herein.

[0102] Treatment method In one embodiment, methods for treating a subject using compositions of this specification, such as polypeptides, conjugated peptides, therapeutic agents, fusion proteins, and combinations thereof, are provided herein.

[0103] Various treatment methods include steps that activate the immune response in the subject.

[0104] Various treatment methods include steps for treating cancer. In some embodiments, the term cancer refers to cells that have the ability to grow autonomously (i.e., an abnormal condition or disease characterized by proliferating cell growth). Non-specific examples of cancer include prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, uterine cancer, bladder cancer, thyroid cancer, ovarian cancer, breast cancer, endometrial cancer, multiple myeloma, melanoma, lymphomas, lung cancer including small cell lung cancer, kidney cancer, colorectal cancer, pancreatic cancer, gastric cancer, and brain cancer.Specific cancers include bladder urothelial carcinoma, breast invasive carcinoma, cholangiocarcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, and skin cutaneous melanoma. This includes melanoma, thyroid cancer, uterine corpus endometrial carcinoma, and uterine carcinosarcoma.

[0105] Various methods involve the step of delivering the composition to a target. Non-limiting examples of delivery methods include intratumor (IT) injection, lymph node induction injection, and tumor embolization via subcutaneous, intramuscular, and intravenous catheters. Delivery methods may also be combined with secondary procedures, which may or may not be related to the disease in which the composition is used. Non-limiting examples of procedures that may be paired with the delivery of the composition include colonoscopies, endoscopies, or various surgical procedures, which may be open surgical procedures or minimally invasive surgical procedures.

[0106] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering an immunomodulatory polypeptide ligated to a delivery particle to the subject, the immunomodulatory polypeptide comprising a conjugating peptide that ligates the immunomodulatory polypeptide to the delivery particle. In some embodiments, the immunomodulatory polypeptide is localized to a target site in the subject. In some embodiments, the immunomodulatory polypeptide does not result in systemic activation of the immune response. In some embodiments, delivery results in fewer side effects than delivery of an immunomodulatory polypeptide not ligated to a delivery particle. Non-limiting examples of immunomodulatory peptides include interleukin (IL), interferon-α (IFNα), interferon-α-2 (IFNα2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), TNF-associated apoptosis-inducing ligand (TRAIL), and interleukin-4 (IL4). In some embodiments, the immunomodulatory polypeptide comprises an interleukin. In some embodiments, the interleukin includes IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the interleukin includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the binding peptide is located at the N-terminus of the interleukin. In some embodiments, the binding peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin includes a first interleukin and a second interleukin. In some embodiments, the binding peptide is located between the first interleukin and the second interleukin. In some embodiments, the method further comprises the step of delivering a second immunomodulatory polypeptide to a subject, the second immunomodulatory polypeptide comprising a second binding peptide that binds the second immunomodulatory polypeptide to a delivery particle, and the second immunomodulatory polypeptide comprising a human leukocyte antigen (HLA) receptor.In some embodiments, the immunomodulatory polypeptide comprises a human leukocyte antigen (HLA) receptor. In some embodiments, the HLA receptor comprises the α chain of the HLA receptor. In some embodiments, the HLA receptor comprises the β chain of the HLA receptor. In some embodiments, the HLA receptor is a class I or class II HLA receptor. In some embodiments, the HLA receptor comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 17-23, 53, or 122. In some embodiments, the binding peptide is located at the N-terminus of the HLA receptor. In some embodiments, the binding peptide is located at the C-terminus of the HLA receptor. In some embodiments, the binding peptide is linked to the immunomodulatory polypeptide via a linker. In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, 124-125, or 127-128. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage site contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the method further includes the step of delivering an antigen to a subject that is related to the disease or condition of the subject. In some embodiments, the antigen is a tumor antigen.In some embodiments of the method, which involves particle delivery, the particles comprise a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound comprises tricalcium phosphate. In some embodiments, the calcium compound comprises β-tricalcium phosphate. In some embodiments, the particles are approximately 1 micron to approximately 150 microns in size. In some embodiments, the particles are approximately 5 microns to approximately 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0107] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering a fusion protein, polypeptide, metabolite, or other composition as herein to the subject. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to the subject. In some embodiments, the binding peptide is located at the N-terminus of the interleukin. In some embodiments, the binding peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the binding peptide is located between the first interleukin and the second interleukin. In some embodiments, the binding peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the linker contains a protease cleavage site.In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0108] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition herein comprising an interleukin (IL). In some embodiments, the interleukin comprises IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs: 15, 16, 94, 95, 96, 97, 98, 99, or 100. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, delivery results in fewer side effects than delivery of a fusion protein not bound to a particle. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to the subject. In some embodiments, the binding peptide is located at the N-terminus of the interleukin. In some embodiments, the binding peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the binding peptide is located between the first interleukin and the second interleukin. In some embodiments, the binding peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1 to 14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0109] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition as herein, comprising interleukin-2 (IL-2). In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16 or 15. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to a subject. In some embodiments, the conjugating peptide is located at the N-terminus of the interleukin. In some embodiments, the conjugating peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the conjugating peptide is located between the first interleukin and the second interleukin. In some embodiments, the conjugating peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the conjugating peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14.In some embodiments, the linker includes sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes protease cleavage sites. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments, the method includes the delivery of particles, the particles comprising a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound comprises tricalcium phosphate. In some embodiments, the calcium compound comprises β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0110] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition as herein, comprising interleukin-12 (IL-12). In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 94. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to a subject. In some embodiments, the conjugating peptide is located at the N-terminus of the interleukin. In some embodiments, the conjugating peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the conjugating peptide is located between the first interleukin and the second interleukin. In some embodiments, the conjugating peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the conjugating peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0111] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition as herein, comprising interleukin-15 (IL-15). In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 96. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to a subject. In some embodiments, the conjugating peptide is located at the N-terminus of the interleukin. In some embodiments, the conjugating peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the conjugating peptide is located between the first interleukin and the second interleukin. In some embodiments, the conjugating peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the conjugating peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0112] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 24. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0113] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 114. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0114] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 25. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0115] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 26. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0116] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 27. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0117] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 28. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0118] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 29. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0119] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 30. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0120] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 31. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0121] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 32. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0122] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 33. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0123] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 34. The method may further include the step of delivering particles to the subject, and optionally, the fusion protein is bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein that is not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method that involve particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0124] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 35. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0125] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 54. The method may further include the step of delivering particles to the subject, and optionally, the fusion protein is bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein that is not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0126] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 55. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0127] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 56. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0128] In some embodiments, a method is provided for activating an immune response in a subject requiring activation of the immune response, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 57. The method may further include the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments of the method, which involves the delivery of particles, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0129] In some embodiments, methods are provided for activating an immune response in subjects requiring activation of an immune response, the method comprising the step of treating the subject with a metabolite containing an interleukin. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 115. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 116. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 117. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 118. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 119. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 120.In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 121. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 126. The metabolite may be released from a larger polypeptide (e.g., a fusion protein as used herein) after cleavage by a protease. The protease may be furin, caspase, cathepsin, or MMP. In some embodiments, the protease cleavage site includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs.

[0130] In some embodiments, a method is provided for treating cancer in a subject requiring treatment, the method comprising the step of delivering an immunomodulatory polypeptide ligated to a delivery particle to the subject, the immunomodulatory polypeptide comprising a conjugating peptide that ligates the immunomodulatory polypeptide to the delivery particle. In some embodiments, the immunomodulatory polypeptide is localized to a target site in the subject. In some embodiments, the immunomodulatory polypeptide does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of an immunomodulatory polypeptide not ligated to a delivery particle. Non-limiting examples of immunomodulatory peptides include interleukins (IL), interferon-α (IFNα), interferon-α-2 (IFNα2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), TNF-associated apoptosis-inducing ligand (TRAIL), and interleukin-4 (IL4). In some embodiments, the immunomodulatory polypeptide comprises an interleukin. In some embodiments, the interleukin comprises IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 15-16. In some embodiments, the binding peptide is located at the N-terminus of the interleukin. In some embodiments, the binding peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin contains a first interleukin and a second interleukin. In some embodiments, the binding peptide is located between the first interleukin and the second interleukin. In some embodiments, the method further comprises the step of delivering a second immunomodulatory polypeptide to a subject, the second immunomodulatory polypeptide comprising a second binding peptide that binds the second immunomodulatory polypeptide to a delivery particle, and the second immunomodulatory polypeptide comprising a human leukocyte antigen (HLA) receptor. In some embodiments, the immunomodulatory polypeptide comprises a human leukocyte antigen (HLA) receptor.In some embodiments, the HLA receptor includes the α chain of the HLA receptor. In some embodiments, the HLA receptor includes the β chain of the HLA receptor. In some embodiments, the HLA receptor is a class I or class II HLA receptor. In some embodiments, the HLA receptor includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 17-23, 53, or 122. In some embodiments, the binding peptide is located at the N-terminus of the HLA receptor. In some embodiments, the binding peptide is located at the C-terminus of the HLA receptor. In some embodiments, the binding peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage site contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the method further includes the step of delivering an antigen to a subject that is associated with the disease or illness of the subject. In some embodiments, the antigen is a tumor antigen. In some embodiments, the method includes the delivery of particles, the particles include a calcium compound.Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0131] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering a fusion protein, polypeptide, metabolite, or other composition as herein to the subject. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to the subject. In some embodiments, the binding peptide is located at the N-terminus of the interleukin. In some embodiments, the binding peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the binding peptide is located between the first interleukin and the second interleukin. In some embodiments, the binding peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. In some embodiments, the linker contains a protease cleavage site.In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0132] In some embodiments, a method is provided for treating cancer in a subject requiring treatment, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition as herein, comprising an interleukin (IL). In some embodiments, the interleukin comprises IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NOs. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of the immune response. In some embodiments, delivery results in fewer side effects than delivery of a fusion protein not bound to a particle. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to the subject. In some embodiments, the binding peptide is located at the N-terminus of the interleukin. In some embodiments, the binding peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the binding peptide is located between the first interleukin and the second interleukin. In some embodiments, the binding peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1 to 14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0133] In some embodiments, a method is provided for treating cancer in subjects requiring cancer treatment, the method comprising the step of delivering a fusion protein, polypeptide, metabolite, or other composition of this specification comprising interleukin-2 (IL-2) to the subject. In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 16 or 15. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to a subject. In some embodiments, the conjugating peptide is located at the N-terminus of the interleukin. In some embodiments, the conjugating peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the conjugating peptide is located between the first interleukin and the second interleukin. In some embodiments, the conjugating peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the conjugating peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0134] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition as herein, comprising interleukin-12 (IL-12). In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 94. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to a subject. In some embodiments, the conjugating peptide is located at the N-terminus of the interleukin. In some embodiments, the conjugating peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the conjugating peptide is located between the first interleukin and the second interleukin. In some embodiments, the conjugating peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the conjugating peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0135] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to the subject a fusion protein, polypeptide, metabolite, or other composition as herein, comprising interleukin-15 (IL-15). In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 96. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles, for example, via a fusion protein binding peptide. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to a subject. In some embodiments, the conjugating peptide is located at the N-terminus of the interleukin. In some embodiments, the conjugating peptide is located at the C-terminus of the interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the conjugating peptide is located between the first interleukin and the second interleukin. In some embodiments, the conjugating peptide is linked to an immunomodulatory polypeptide via a linker. In some embodiments, the conjugating peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1-14.In some embodiments, the linker includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 36-52, 101-113, or 124-125. In some embodiments, the linker includes a protease cleavage site. In some embodiments, the protease cleavage sites include sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 47-50, 106-108, 112-113, and 124-125. In some embodiments where the method involves particle delivery, the particles include a calcium compound. The calcium compound includes, but is not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is approximately 40 microns.

[0136] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 24. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0137] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 114. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0138] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 25. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0139] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 26. The method may further comprise the step of delivering particles to the subject, optionally, the fusion protein being bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particles are about 40 microns in size.

[0140] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 27. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0141] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 28. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0142] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 29. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0143] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 30. The method may further comprise the step of delivering particles to the subject, the fusion protein being bound to the particles (optionally). In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0144] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 31. The method may further include the step of delivering particles to the subject, the fusion protein being bound to the particles (optionally). In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further includes the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0145] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 32. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0146] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 33. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0147] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 34. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0148] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 35. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0149] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 54. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0150] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 55. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0151] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 56. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0152] In some embodiments, a method is provided for treating cancer in subjects requiring treatment, the method comprising the step of delivering to a subject a fusion protein containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 57. The method may further comprise the step of delivering particles to the subject, the fusion protein being optionally bound to the particles. In some embodiments, the fusion protein is localized to a target site in the subject. In some embodiments, the fusion protein does not result in systemic activation of an immune response. In some embodiments, the delivery results in fewer side effects than the delivery of a fusion protein not bound to particles. In some embodiments, the method further comprises the step of administering to the subject an immune checkpoint inhibitor, such as an anti-PD-1 antibody. In some embodiments where the method involves particle delivery, the particles contain a calcium compound. Calcium compounds include, but are not limited to, calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, and hydroxyapatite. In some embodiments, the calcium compound includes tricalcium phosphate. In some embodiments, the calcium compound includes β-tricalcium phosphate. In some embodiments, the particles are about 1 micron to about 150 microns in size. In some embodiments, the particles are about 5 microns to about 50 microns in size. In some embodiments, the particle size is about 40 microns.

[0153] In some embodiments, a method is provided for treating cancer in a subject requiring treatment, the method comprising the step of treating the subject with a metabolite comprising an interleukin. In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 115. In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 116. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 117. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 118. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 119. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 120. In some embodiments, the interleukin includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 121.In some embodiments, the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 126. The metabolite may be released from a larger polypeptide (e.g., a fusion protein as used herein) after cleavage by a protease. The protease may be furin, caspase, cathepsin, or MMP. In some embodiments, the protease cleavage site includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 47-50, 106-108, 112-113, 124-125, or 127-128. In some embodiments, the metabolite is localized to a target site in the subject. In some embodiments, this metabolite does not result in systemic activation of the immune response. In some embodiments, the method further includes administering an immune checkpoint inhibitor, such as an anti-PD-1 antibody, to the subject.

[0154] In some embodiments, a method is provided for activating an immune response in a subject that requires activation of an immune response to treat cancer, the method comprising the step of delivering an anticancer agent conjugated to particles containing a calcium compound to the subject. In some embodiments, a method is provided for treating cancer in a subject that requires treatment of cancer, the method comprising the step of delivering an anticancer agent conjugated to particles containing a calcium compound to the subject. In some embodiments, the anticancer agent is localized to a target site in the subject. In some embodiments, the anticancer agent does not result in systemic activation of the immune response. In some embodiments, the delivery results in fewer side effects than the delivery of an anticancer agent that is not conjugated to delivery particles. In some embodiments, the method results in cancer-specific immune activation. In some embodiments, the anticancer agent comprises a conjugating peptide that binds to the calcium compound in the particles. In some embodiments, the calcium compound comprises calcium phosphate, calcium carbonate, calcium oxide, calcium silicate, hydroxyapatite, metal oxide, or a material passivated with oxygen or nitrogen. In some embodiments, the calcium compound comprises tricalcium phosphate. In some embodiments, the calcium compound comprises β-tricalcium phosphate. In some embodiments, the particles are approximately 1 to 150 microns in size. In some embodiments, the particles are approximately 5 to 50 microns in size. In some embodiments, the particle size is approximately 40 microns. In some embodiments, the anticancer drug contains protease cleavage sites. In some embodiments, the protease cleavage sites are cleaved by T cell proteases. In some embodiments, the protease cleavage sites are cleaved by cancer cell proteases in the subject. In some embodiments, the protease cleavage site includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 47-50, 106-108, 112-113, 124-125, or 127-128.In some embodiments, the method further includes the step of delivering an antigen (tumor antigen) associated with the cancer of the subject to a subject. In some embodiments, the anticancer agent is an immunomodulatory polypeptide. Non-limiting examples of immunomodulatory peptides include interleukins (IL), interferon-α (IFNα), interferon-α-2 (IFNα2), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-4 (IL4). In some embodiments, the immunomodulatory polypeptide includes an interleukin. In some embodiments, the interleukin includes IL2, IL12, IL21, IL15, IL7, IL24, or IL28. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 15-16. In some embodiments, the interleukin contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence numbers 15, 16, 94, 95, 96, 97, 98, 99, or 100. In some embodiments, the anticancer agent comprises a binding peptide located at the N-terminus of an interleukin. In some embodiments, the anticancer agent comprises a binding peptide located at the C-terminus of an interleukin. In some embodiments, the interleukin comprises a first interleukin and a second interleukin. In some embodiments, the anticancer agent comprises a binding peptide located between the first interleukin and the second interleukin. In some embodiments, the method further comprises the step of delivering a second anticancer agent to a subject, the second anticancer agent comprising a second immunomodulatory polypeptide comprising a human leukocyte antigen (HLA) receptor. In some embodiments, the anticancer agent comprises a human leukocyte antigen (HLA) receptor. In some embodiments, the HLA receptor comprises the α-chain of the HLA receptor.In some embodiments, the HLA receptor includes the β-chain of the HLA receptor. In some embodiments, the HLA receptor is a class I or class II HLA receptor. In some embodiments, the HLA receptor includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 17-23, 53, or 122. In some embodiments, the anticancer agent includes a binding peptide located at the N-terminus of the HLA receptor. In some embodiments, the anticancer agent includes a binding peptide located at the C-terminus of the HLA receptor. In some embodiments, the anticancer agent includes a binding peptide bound to a particle. In some embodiments, the binding peptide contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 1 to 14. In some embodiments, the method further includes the step of delivering an antigen associated with the cancer of the subject. In some embodiments, the antigen is a tumor antigen.

[0155] Treatment method: Combination therapy In one embodiment, methods for treating a subject using compositions of this specification, such as polypeptides, conjugated peptides, therapeutic agents, fusion proteins, and combinations thereof, are provided herein.

[0156] In some embodiments, a method of treating a subject using the compositions described herein includes administering to a subject a fusion protein having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with any one of the fusion proteins in Table 3, in combination with an antigenic peptide such as the antigenic peptide in Table 2, and a peptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the peptides in Table 2.

[0157] In some embodiments, a method of treating a subject using the compositions herein includes administering to a subject a fusion protein having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to any one of the fusion proteins in Table 3, in combination with an immune checkpoint inhibitor. In some non-limiting embodiments, the immune checkpoint inhibitor includes an anti-programmed cell death protein 1 (anti-PD-1) antibody, an anti-programmed cell death ligand 1 (anti-PD-L1) antibody, an anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) antibody, or a combination thereof. Non-exclusive examples of anti-PD1 antibodies include pembrolizumab (e.g., Keytruda), toripalimab, nivolumab (e.g., Opdivo), cemiplimab (e.g., Libtayo), dostarlimab (e.g., Jemperli), cindilimab, camrelizumab, tislelizumab, penpulimab, zimberelimab, prolgolimab, and retifanlimab. Non-restrictive anti-PD-L1 inhibitors include atezolizumab (e.g., Tecentriq), durvalumab (e.g., Imfinzi), envafolimab, sugemalimab, and avelumab (e.g., Bavencio). Non-restrictive anti-CTLA-4 inhibitors include ipilimumab (e.g., Yervoy) and tremelimumab.

[0158] In some embodiments, a method of treating a subject using the compositions described herein includes administering to a subject a fusion protein containing the fusion protein of Table 3, or a fusion protein having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the fusion protein of Table 3, in combination with a peptide of Table 2, or a peptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the peptide of Table 2.

[0159] In some embodiments, a method of treating a subject using the compositions described herein includes administering to a subject a fusion protein containing SEQ ID NO: 24, or a fusion protein having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 24, in combination with a peptide from Table 2, or a peptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a peptide from Table 2.

[0160] In some embodiments, a method of treating a subject using the compositions of this specification includes administering to a subject a fusion protein containing SEQ ID NO: 114, or a fusion protein having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 114, in combination with a peptide from Table 2, or a peptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a peptide from Table 2.

[0161] In some embodiments, a method of treating a subject using the compositions described herein includes administering to a subject a fusion protein containing SEQ ID NO: 24, or a fusion protein having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to SEQ ID NO: 24, in combination with an immune checkpoint inhibitor.

[0162] In some embodiments, a method of treating a subject using the compositions described herein includes administering to a subject a fusion protein containing SEQ ID NO: 24, or a fusion protein having at least 80%, 81%, 82%...

Claims

1. A method for activating an immune response and / or treating cancer in a subject requiring activation of an immune response and / or treatment of cancer, the method comprising the step of delivering to the subject an immunomodulatory polypeptide comprising an interleukin and particles comprising a calcium compound.

2. The method according to claim 1, wherein the immunomodulatory polypeptide comprises a binding peptide that binds to the calcium compound of the particle.

3. The method according to claim 2, wherein the binding peptide comprises a sequence that is at least 80% identical to any one of SEQ ID NOs. 12-14 and 1-11.

4. The method according to claim 2 or 3, wherein the immunomodulatory polypeptide comprises a protease cleavage site located between the interleukin and the binding peptide, and the protease cleavage site is cleaved by a protease of a T cell and / or cancer cell.

5. The method according to claim 4, wherein the protease cleavage site includes (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113.

6. The immunomodulatory polypeptide comprises a linker located between the interleukin and the binding peptide, wherein the linker has a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 42, and / or sequences that are identical to sequence number 111 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, (ii) sequences that are identical to sequence number 43 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, or 89% Sequences that are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104, sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 104, and / or sequence number The method according to any one of claims 2 to 5, comprising an array that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to array 105, or (iii) one or more of arrays 36-52, 124-125, and 101-113.

7. The method according to any one of claims 1 to 6, wherein the interleukin includes a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 16, 15, and 94 to 100.

8. The method according to any one of claims 1 to 7, wherein the interleukin includes IL2, IL12, IL21, IL15, IL7, IL24, or IL28.

9. The method according to any one of claims 1 to 8, wherein the immunomodulatory polypeptide is localized to a target site in the target, the immunomodulatory polypeptide does not cause systemic activation of the immune response, the step of delivering the polypeptide to the target results in fewer side effects than the step of delivering the immunomodulatory polypeptide to the target without the particles, and / or the method results in cancer-specific immune activation.

10. The method according to any one of claims 1 to 9, comprising the step of administering an immune checkpoint inhibitor to the subject.

11. The method according to claim 10, wherein the immune checkpoint inhibitor comprises an anti-PD1 antibody.

12. The method according to any one of claims 1 to 11, wherein the cancer is malignant melanoma, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, uterine cancer, bladder cancer, thyroid cancer, ovarian cancer, or breast cancer.

13. The method according to any one of claims 1 to 12, wherein delivery is by intratumor (IT) injection, lymph node induction injection, subcutaneous, intramuscular, or intravenous catheter-mediated tumor embolization.

14. The method according to any one of claims 1 to 13, wherein delivery is performed during surgery, colonoscopy, or endoscopy.

15. A composition comprising calcium compound particles and a peptide fusion protein containing a binding peptide linked to an immunomodulatory polypeptide, wherein the binding peptide is bound to the calcium compound, linking the peptide fusion protein to the calcium compound particles, and optionally, the immunomodulatory polypeptide comprises interleukin (IL), interferon α (IFNα), interferon α-2 (IFNα2), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), or interleukin 4 (IL4).

16. The composition according to claim 15, wherein the binding peptide comprises one or more sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs. 12-14 and 1-11.

17. The composition according to claim 15 or claim 16, wherein the immunomodulatory polypeptide comprises an interleukin, and the interleukin comprises IL2, IL12, IL21, IL15, IL7, IL24, or IL28.

18. The composition according to claim 15 or claim 16, wherein the immunomodulatory polypeptide comprises an interleukin, and the interleukin comprises a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 16, 15, and 94-100.

19. The composition includes a linker position between the binding peptide and the immunomodulatory polypeptide, wherein the linker is (i) identical to at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (i) SEQ ID NO: 42, and / or identical to at least 80%, 81%, 82%, 83% identical to SEQ ID NO:

111. (ii) Sequences that are identical by %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, (ii) Sequences that are identical by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, to sequence number 4 For 3, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical sequences; for sequence number 104, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 9 The composition according to any one of claims 15 to 18, comprising a sequence that is 9% identical and / or a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 105, or (iii) one or more of sequence numbers 36-52, 124-125, and 101-113.

20. The composition according to any one of claims 15 to 19, wherein the composition comprises a protease cleavage site located between the binding peptide and the immunomodulatory polypeptide, the protease cleavage site comprising (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113.

21. The method according to any one of claims 1 to 14, or the composition according to any one of claims 15 to 20, wherein the particles are approximately 1 micron to approximately 100 microns in size.

22. The calcium compound comprises β-tricalcium phosphate, according to the method according to any one of claims 1 to 14 or 21, or the composition according to any one of claims 15 to 21.

23. Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, or Formula 12: TA-BP (formula 1), TA-L-BP (formula 2), BP-TA (formula 3), BP-L-TA (formula 4), TA1-L1-BP-L2-TA2 (Formula 5), TA1-BP-TA2 (formula 6), TA1-L1-BP-TA2 (Formula 7), TA1-BP-L1-TA2 (Formula 8), BP1-L1-TA-L2-BP2 (Formula 9), BP1-TA-BP2 (formula 10), BP1-L1-TA-BP2 (Formula 11), BP1-TA-L1-BP2 (Formula 12) It is a fusion protein, In the formula, each TA, TA1, and TA2 is independently a therapeutic agent, each L, L1, and L2 is independently a linker, and each BP, BP1, and BP2 is independently a binding peptide. Each therapeutic agent independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the immunomodulators, anticancer agents, antigen peptides, or sequence numbers 16, 15, 17-23, 53, 58-100, and 122. Each bound peptide independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 12, 13, 14, 1-11. A fusion protein in which each linker independently contains (i) a furin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of sequence numbers 36-52, 124-125, 127-128, and 101-113.

24. A polypeptide comprising a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of sequence numbers 24, 114, 25-35, 55-57, 126, and 115-121.

25. Polypeptides comprising (i) a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSTSTVGADSTHHRPVTLIADSTHHSPWTAAESTSKKRPFS), and (ii) SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLLDLQMILN A polypeptide comprising interleukin-2 having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to (GINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT).

26. Polypeptides comprising (i) a conjugated peptide containing a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13 (AAESTSKKRPFS) and (ii) SEQ ID NO: 16 (APTSSSTKKTQLQLEHLLLD A polypeptide comprising interleukin-2 having a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to LQMILNGINNYKNPKLTRMMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT.

27. It is a polypeptide, (i) A sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 16 (APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRRPRDLISNINVIVLEELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT), (ii) (a) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 12, (b) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 13, (c) Sequences that are identical to sequence number 14 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, (d) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 1 (ILAETTHHRPWS), (e) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 2 (STADTSHHRPST), (f) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 3 (VGADSTHHRPVT), (g) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 4 (LIADSTHHSPWT), (h) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 5 (AAESTSKKRPFS), (i) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 7 (VIGESTHHRPWS), (j) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 10 (ILAESTHHKPWT), (k) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 8 (IIGESSHHKPFT), (l) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 9 (GLGDTTHHRPWG), (m) Sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 6 (LLADTTHHRPWT), (n) A sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to sequence number 11, or Combinations containing two or more sequences from (o)(a) to (n) and polypeptides, including

28. The polypeptide comprises a linker located between (i) and (ii), wherein the linker is identical to (i) sequence 42 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and / or identical to sequence 111 by at least 80%, 81%, 82%, 83%, 84%, Sequences that are 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical; (ii) Sequence number 103 is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical; Sequence number 43 is at least For sequences, sequence number 104, that are identical by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, then for sequences, sequence number 104, that are identical by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. A polypeptide according to any one of claims 25 to 27, comprising (iii) a sequence that is identical to sequence 105 by at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or (iii) one or more of sequence numbers 36-52, 124-125, and 101-113.

29. The polypeptide according to any one of claims 25 to 27, wherein the polypeptide includes a protease cleavage site located between (i) and (ii), and the protease cleavage site includes (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113.

30. The polypeptide according to claim 29, wherein the cleavable linker comprises SEQ ID NO: 106 (RKKR) or SEQ ID NO: 113 (RKKRSTDEVDGAPPLGL).

31. A polypeptide comprising (i) a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 13 (AAESTSKKRPFSILAETTHHRPWSSTADTSHHRRPSTVGADSTHHRRPVTLIADDSTHHSPWTAAAESTSKKRPFS), (ii) a first interleukin-2, and (iii) a second interleukin-2, wherein the first interleukin-2 and the second i Each of the interleukin-2 molecules independently contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to Sequence ID No. 16 (APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT).

32. The polypeptide according to claim 31, wherein (i) is located between (ii) the first interleukin-2 and (iii) the second interleukin-2.

33. The polypeptide according to claim 31 or 32, wherein (i) and (ii) are linked via a first linker, and (i) and (iii) are linked via a second linker.

34. The polypeptide according to claim 33, wherein the first linker comprises one or more of sequence numbers 36-52, 124-125, and 101-113, and the second linker comprises one or more of sequence numbers 36-52, 124-125, and 101-113.

35. The polypeptide according to claim 33, wherein the first linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more of SEQ ID NOs: 103, 109, and 104, and the second linker contains a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one or more of SEQ ID NOs: 103, 109, and 104.

36. The polypeptide according to any one of claims 33 to 35, wherein the first linker comprises (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113, and the second linker comprises (i) a fulin cleavage site, (ii) a caspase cleavage site, (iii) a matrix metalloproteinase cleavage site, (iv) a cathepsin cleavage site, and (v) one or more of SEQ ID NOs: 47-50, 106-108, 124-125, 127-128, and 112-113.

37. The polypeptide according to any one of claims 33 to 36, wherein the first linker includes a Fuhrn cleavage site and the second linker includes a Fuhrn cleavage site.

38. Polypeptide, such as SEQ ID NO: 13 (AAESTSKKRPFSILAETTHHRPWSSTADTSHHRPSSTVGGADSTHHRPVTLIADSTHHSPWTAAAESTSKKRPFS), SEQ ID NO: 12 (ILAETTHHRPWSSTADTSHHRPSSTVGGADSTHHRPVTLIADSTHHSPWTAAAESTSKKRPFS), or SEQ ID NO: 14 (LIADST Polypeptides comprising a sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to HHSPWT.

39. A nucleic acid encoding the composition according to any one of claims 15 to 20, the fusion protein according to claim 23, or the polypeptide according to any one of claims 24 to 38.

40. A vector comprising the nucleic acid described in claim 39.

41. A kit comprising particles comprising the composition according to any one of claims 15 to 20, the fusion protein according to claim 23, or the polypeptide according to any one of claims 24 to 38, and a calcium compound.

42. A method for treating an object requiring treatment, the method comprising the step of delivering to the object a composition according to any one of claims 15 to 20, a fusion protein according to claim 23, a polypeptide according to any one of claims 24 to 38, or a kit according to claim 41.

43. The method according to claim 42, further comprising the step of administering an immune checkpoint inhibitor to the subject.

44. The method according to claim 43, wherein the immune checkpoint inhibitor comprises an anti-PD1 antibody.

45. The method according to any one of claims 42 to 44, wherein the method of treatment includes a step of treating cancer in the subject, and the cancer is malignant melanoma, renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, uterine cancer, bladder cancer, thyroid cancer, ovarian cancer, or breast cancer.

46. The method according to any one of claims 42 to 45, wherein the method of the treatment includes a step of activating an immune response in the subject.

47. The method according to any one of claims 42 to 46, wherein delivery is by intratumor (IT) injection, induction injection into lymph nodes, subcutaneous, intramuscular, or tumor embolization via a venous catheter.

48. The method according to any one of claims 42 to 47, wherein delivery is performed during surgery, colonoscopy, or endoscopy.

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