Activatable il-18 immunocytokines and uses thereof

Abstract

The present disclosure relates to activatable IL-18 immunocytokine compositions comprising antibodies or antigen binding fragments specific for immune cell antigens and activatable IL-18 polypeptides. Also provided herein are methods of treatment with and methods of manufacture of activatable immunocytokine compositions. Activatable IL-18 polypeptides usable in immunocytokines are also encompassed by the present disclosure.

Description

[0001] ES Docket No.94917-0155.737601WO PATENT APPLICATION ACTIVATABLE IL-18 IMMUNOCYTOKINES AND USES THEREOF Inventor(s): PATTABIRAMAN, Vijaya Raghavan, KREFT, Bertolt, GOEPFERT, Arnaud ONGARO, Tiziano CARRALOT, Jean-Philippe MARTIN, Kea Address: Bright Peak Therapeutics AG, Hegenheimermattweg 167D 4123 Allschwil, Switzerland Entity: Large business concern EVERSHEDS SUTHERLAND 999 Peachtree St NE Atlanta, GA 30309 (404) 853-8000 (Main) Electronically Filed on: August 23, 2024

[0002] ES Docket No.94917-0155.737601WO ACTIVATABLE IL-18 IMMUNOCYTOKINES AND USES THEREOF CROSS REFERENCE This application claims the benefit of U.S. Provisional Application No. 63 / 534,273 filed August 23, 2023, which application is incorporated herein by reference in its entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on August 21, 2024, is named 94917-01585_737601WO_SL.xml and is 490,308 bytes in size. BRIEF SUMMARY Described herein are activatable immunocytokine compositions which contain an antibody or antigen binding fragment thereof, an activatable interleukin 18 (Act-IL-18) polypeptide and a linker. The antibody or antigen binding fragment thereof can be specific for (e.g., binds specifically to) an immune cell associated antigen. In some embodiments, the Act-IL-18 polypeptide comprises an artificial polypeptide attached to the base sequence of a mature IL-18 which, when attached, lowers the IL-18-related activity of the molecule. In some embodiments, the artificial polypeptide is cleaved by a protease, such as a protease upregulated in a tumor microenvironment, thereby removing all or a portion of the artificial polypeptide and enhancing the IL-18 related activity (e.g., IL-18 receptor signaling) of the molecule. In some embodiments, an activatable immunocytokine may exhibit fewer side effects or off-target effects compared to a non-activatable immunocytokine owing to the lessened activity of the IL-18 portion of the molecule before cleavage activation, thus providing advantages in some contexts over other immunocytokines. An exemplary, non-limiting mechanism of action of an activatable immunocytokine provided herein is shown in FIG. 1. In the exemplary embodiment, the immunocytokine composition comprises an anti-PD-1 antibody as the antibody or antigen binding fragment of the activatable immunocytokine. In this embodiment, the anti-PD-1 antibody portion of the immunocytokine selectively binds to PD-1 present on the surface of an activated T cell (e.g., a CD8+T cell). This binding prevents the checkpoint interaction of PD-1 and PD-L1 / 2, thus preventing attenuation of activity of the T cell. Concomitantly, after activation of the IL-18 portion of the immunocytokine by tumor microencironment proteases, the IL-18 concentration is -2- 49194109.1 ES Docket No.94917-0155.737601WO effectively in a high local concentration near the T-cell due to the linkage, further activates the T cell through IL-18R signaling. The activatable immunocytokine shown in this figure is depicted with two activatable IL-18 polypeptides attached to the antibody (DAR2), however activatable immunocytokines having only a single activatable IL-18 polypeptide attached (DAR1) are also expressly contemplated as within the scope of the instant disclosure. While the exemplary embodiment shows the mechanism of action of an anti-PD-1 antibody, antibodies or antigen binding fragments specific for other immune antigens provided herein can function according to a similar mechanism. Further descriptions of activatable IL-18 polypeptides by themselves are described elsewhere in the instant disclosure. In one aspect, provided herein, is an activatable immunocytokine composition, comprising: an Act-IL-18 polypeptide; an antibody or an antigen binding fragment thereof; and a linker, wherein the linker comprises: a first point of attachment to the antibody or antigen binding fragment thereof; and a second point of attachment to the Act-IL-18 polypeptide. The antibody or antigen binding fragment thereof can be specific for an immune cell associated antigen. The Act-IL-18 polypeptide can comprise an artificial polypeptide attached to an IL-18 polypeptide. The artificial polypeptide can comprise a protease cleavage site. Cleavage at the protease cleavage site can convert the Act-IL-18 into an active form of the IL-18 polypeptide. In some embodiments, when the artificial polypeptide is intact, the Act-IL-18 is inactive. The Act-IL-18 polypeptide can be activated in response to certain conditions or stimuli found in a target area of a subject after administration. In some embodiments, the artificial polypeptide is cleaved at the protease cleavage site under one or more conditions associated with a desired target area (e.g., a tumor microenvironment), thus releasing an active IL-18 polypeptide. In some embodiments, the protease cleavage site is preferentially cleaved at or near a target tissue of a subject. In some embodiments, the protease cleavage site is preferentially cleaved in or near a tumor microenvironment. In some embodiments, cleavage at the protease cleavage site enhances an IL-18 related activity of the activatable immunocytokine. In some embodiments, cleavage at the protease cleavage site converts the Act-IL-18 polypeptide into an activated form of the IL-18 polypeptide with an enhanced IL-18 related activity. In some embodiments, the specific cleavage site is specifically cleaved by a protease. In some embodiments, the protease is found at higher concentrations and / or demonstrates higher proteolytic activity within the tumor microenvironment relative to non-tumor tissue. In some -3- 49194109.1 ES Docket No.94917-0155.737601WO embodiments, the protease is selected from: kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, proteinase 3 (PR-3), granzyme M, a calpain, a matrix metalloproteinase (MMP), a disintegrin and metalloproteinase (ADAM), a fibroblast activation protein alpha (FAP), a plasminogen activator, a cathepsin, a caspase, a tryptase, and a tumor cell surface protease. In some embodiments, the Act-IL-18 polypeptide comprises a protease recognition sequence comprising the protease cleavage site. In some embodiments, the protease recognition sequence has a sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a peptide sequence set forth in Table 2A or 2B. In some embodiments, the protease recognition sequence comprises the amino acid sequence set forth in any one of SEQ ID NOs: 646, 647, 648, 649, 650, 651, 652, 653, 657, 658, or 659. In some embodiments, the cleavage at the protease cleavage site removes the entire artificial polypeptide from the IL-18 polypeptide. In some embodiments, the cleavage results in a of In at 4, ES Docket No.94917-0155.737601WO 5, 6, 7, 8, 9, or 10 amino acid residues of the artificial polypeptide attached to the IL-18 polypeptide. In some embodiments, the artificial polypeptide comprises multiple protease cleavage C- 18 18 the the ID is ES Docket No.94917-0155.737601WO In some embodiments, the artificial polypeptide is connected to the N-terminus of the IL-18 polypeptide. 18 In as to of ES Docket No.94917-0155.737601WO FIG.3B is analogous to FIG.3A, but the artificial polypeptide is linked to the C-terminus of the IL-18 polypeptide. In some embodiments, the active form of the IL-18 polypeptide displays reduced binding to IL-18 binding protein (IL-18BP), compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide displays enhanced binding to IL-18R or ability to activate IL-18R, compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide displays a binding to IL-18R or ability to activate IL-18R which is reduced by at most 100-fold relative to WT IL-18. In some embodiments, the IL-18 polypeptide comprises one or more modifications to the sequence set forth in SEQ ID NO: 1. In some embodiments, the IL-18 polypeptide comprises an 18 the 3, in ES Docket No.94917-0155.737601WO higher than the activated form of the IL-18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is from about 10-fold higher to about 100-fold higher than the activated form of the IL-18 polypeptide. In some embodiments, the activated form of the IL-18 polypeptide exhibits a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is within about 10-fold of the IL-18 polypeptide. In some embodiments, the Act-IL-18 polypeptide exhibits a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is at least 10-fold greater than WT IL-18. In some embodiments, the linker comprises a polymer. In some embodiments, the polymer comprises a water-soluble polymer. In some embodiments, the water-soluble polymer comprises poly(alkylene oxide), polysaccharide, poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), or a combination thereof. In some embodiments, the water-soluble polymer comprises poly(ethylene glycol). In some embodiments, the polymer has an average molecular weight of about 0.1 kDa to 2kDa. In some embodiments, the polymer has an average molecular weight of at least about 0.1 kDa, at least about 0.5 kDa, at least about 1 kDa, at least about 5 kDa, at least about 10 kDa, at least about 20 kDa, at least about 30 kDa, at least 40 kDa, at least 50 kDa, at least 60 kDa, at least 70 kDa, at least 80 kDa, at least 90 kDa, at least 100 kDa, at least 120 kDa, at least 130 kDa, at least 140 kDa, at least 150 kDa, or more. In some embodiments, the second point of attachment is at a residue which is not the N- terminus or the C-terminus of the IL-18 polypeptide. In some embodiments, the second point of attachment is to a residue in the region of residues 2-156 of the IL-18 polypeptide, wherein residue position numbering is based on SEQ ID NO: 1. In some embodiments, the second point of attachment is to a residue in the region of residues 38-144 of the IL-18 polypeptide. In some embodiments, the second point of attachment is at residue 38, 68, 69, 70, 76, 78, 85, 86, 95, 98, 121, 127, or 144 of the IL-18 polypeptide. In some embodiments, the second point of attachment is at residue 68, 69, 70, 85, 86, 95, or 98 of the IL-18 polypeptide. In some embodiments, the second point of attachment is at residue 68 of the IL-18 polypeptide. In some embodiments, the IL-18 polypeptide comprises an amino acid substitution at the second point of attachment. In some embodiments, the amino acid substitution at the second point of attachment is for an unnatural amino acid. In some embodiments, the amino acid substitution at the second point of attachment -8- 49194109.1 ES Docket No.94917-0155.737601WO is for a natural amino acid. In some embodiments, the amino acid substitution at the second point of attachment is E69C, K70C, E85C, M86C, T95C, or D98C. In some embodiments, the first point of attachment is at a position of a K246 amino acid residue, a K248 amino acid residue, a K288 amino acid residue, a K290 amino acid residue, or a K317 amino acid residue of the Fc region (EU numbering). In some embodiments, wherein the first point of attachment is at the K248 amino acid residue of the Fc region (EU numbering). In some embodiments, the antibody or antigen binding fragment thereof is a monoclonal antibody, a humanized antibody, a grafted antibody, a chimeric antibody, a human antibody, a de- immunized antibody, or a bispecific antibody. In some embodiments, the antibody or antigen binding fragment thereof an antigen binding fragment, wherein the antigen binding fragment comprises a Fab, a Fab', a F(ab')2, a bispecific F(ab')2, a trispecific F(ab')2, a variable fragment (Fv), a single chain variable fragment (scFv), a dsFv, a bispecific scFv, a variable heavy domain, a variable light domain, a variable NAR domain, bispecific scFv, an AVIMER®, a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a minibody, a maxibody, a camelid, a VHH, a minibody, an intrabody, fusion proteins comprising an antibody portion (a domain antibody), a single chain binding polypeptide, a scFv-Fc, a Fab-Fc, a bispecific T cell engager (BiTE), a tetravalent tandem diabody (TandAb), a Dual-Affinity Re-targeting Antibody (DART), a bispecific antibody (bscAb), a single domain antibody (sdAb), a fusion protein, or a bispecific disulfide-stabilized Fv antibody fragment (dsFv–dsFv′). In some embodiments, the antibody or antigen binding fragment thereof comprises an IgG, an IgM, an IgE, an IgA, an IgD, or is derived therefrom. In some embodiments, the antibody or antigen binding fragment thereof comprises the IgG, and wherein the IgG is an IgG1, an IgG4, or is derived therefrom. In some embodiments, the antibody or antigen binding fragment thereof binds specifically to an immune associated antigen. In some embodiments, the immune cell associated antigen is 4-IBB, B7-H3, B7-H4, BTLA, CD3, CCR8, CD8A, CD8B, CD16A, CD27, CD28, CD33, CD38, CD39, CD40, CD47, CD70, CD80, CD86, CD96, CD163, CLEC-1, CLEVER-1, CTLA-4, D40, GITR, ICOS, ILT2 / 3 / 4, LAG-3, MHCI, MHCII, NKG2A, NKG2D, NKp30, NKp44, NKp46, OX40, PD-1, PD-L1, PD-L2, PSGL- 1, SIGLEC-9, SIGLEC-15, SIRP-α, TCR,TIGIT, TIM-3,VISTA, or VSIG4. In some embodiments, the immune cell associated antigen is PD-1. In some embodiments, the antibody or antigen binding fragment thereof comprises tislelizumab, baizean, 0KVO411B3N, BGB-A317, hu317-1 / IgG4mt2, sintilimab, tyvyt, IBI-308, toripalimab, TeRuiPuLi , terepril, tuoyi, -9- 49194109.1 ES Docket No.94917-0155.737601WO JS-001, TAB-001, tamrelizumab , HR-301210, INCSHR-01210, SHR-1210, temiplimab, cemiplimab-rwlc, 6QVL057INT , H4H7798N, REGN-2810 , SAR-439684, lambrolizumab, pembrolizumab, MK-3475, SCH-900475, h409A11, nivolumab, nivolumab BMS, BMS-936558, MDX-1106, ONO-4538, prolgolimab, forteca, BCD-100, penpulimab, AK-105, zimberelimab, AB-122, GLS-010, WBP-3055, balstilimab, 1Q2QT5M7EO, AGEN-2034, AGEN-2034w, genolimzumab, geptanolimab, APL-501, CBT-501, GB-226, dostarlimab, ANB-011, GSK- 4057190A, P0GVQ9A4S5, TSR-042, WBP-285, serplulimab, HLX-10, CS-1003, retifanlimab, 2Y3T5IF01Z, INCMGA-00012, INCMGA-0012, MGA-012, sasanlimab, LZZ0IC2EWP, PF- 06801591, RN-888, spartalizumab, PDR-001, QOG25L6Z8Z, relatlimab / nivolumab, BMS- 986213, cetrelimab, JNJ-3283, JNJ-63723283, LYK98WP91F, tebotelimab, MGD-013, BCD- 217, BAT-1306, HX-008, MEDI-5752, JTX-4014, cadonilimab, AK-104, BI-754091, pidilizumab, CT-011, MDV-9300, YBL-006, AMG-256, RG-6279, RO-7284755, BH-2950, IBI- 315, RG-6139, RO-7247669, ONO-4685, AK-112, 609-A, LY-3434172, T-3011, AMG-404, IBI- 318, MGD-019, ONCR-177, LY-3462817, RG-7769, RO-7121661, F-520, XmAb-23104, Pd-1- pik, SG-001, S-95016, Sym-021, LZM-009, budigalimab, 6VDO4TY3OO, ABBV-181, PR- ES Docket No.94917-0155.737601WO 3280A, RG-7446, RO-5541267, CAS 1380723-44-3), Sugemalimab (CS-1001, WBP-3155), KN- 046 (CAS 2256084-03-2), APL-502 (CBT-502, TQB-2450), Envafolimab (3D-025, ASC-22, KN- 035, hu56V1-Fc-m1, CAS 2102192-68-5), Bintrafusp alfa (M-7824, MSB-0011359C, NW9K8C1JN3, CAS 1918149-01-5), STI-1014 (STI-A1014, ZKAB-001), PD-L1 t-haNK, A-167 (HBM-9167, KL-A167), IMC-001 (STI-3031, STI-A-1015, STI-A1015, s), HTI-1088 (SHR- 1316), IO-103, CX-072 (CytomX Therapeutics), AUPM-170 (CA-170), GS-4224, ND-021 (NM21-1480, PRO-1480), BNT-311 (DuoBody-PD-L1x4-1BB, GEN-1046), BGB-A333, IBI- 322, NM-01, LY-3434172, LDP, CDX-527, IBI-318, 89Zr-DFO-REGN3504, ALPN-202 (CD80 vIgD-Fc), INCB-086550, LY-3415244, SHR-1701, JS-003 (JS003-30, JS003-SD), HLX-20 (PL2#3), ES-101 (INBRX-105, INBRX-105-1), MSB-2311, PD-1-Fc-OX40L (SL-279252, TAK- 252), FS-118, FS118 mAb2, LAG-3 / PD-L1 mAb2), FAZ-053 (LAE-005), Lodapolimab (LY- 3300054, NR4MAD6PPB, CAS 2118349-31-6), MCLA-145, BMS-189, Cosibelimab (CK-301, TG-1501, CAS 2216751-26-5), IL-15Ralpha-SD / IL-15 (KD-033), WP-1066 (CAS 857064-38-1), BMS-936559 (MDX-1105), BMS-986192, RC-98, CD-200AR-L (CD200AR-L), ATA-3271, IBC-Ab002, BMX-101, AVA-04-VbP, ACE-1708, KY-1043, ACE-05 (YBL-013), ONC-0055 (ONC0055, PRS-344 S-095012), TLJ-1-CK, GR-1405, PD1ACR-T, N-809 (N-IL15 / PDL1), CB- 201, MEDI-1109, AVA-004 (AVA-04), CA-327, ALN-PDL, KY-1003, CD22(aPD-L1)CAR-T cells (SL-22P), ATA-2271 (M28z1XXPD1DNR CAR T cells), or a modified version thereof. In some embodiments, the antibody is Durvalumab, Atezolizumab, or Avelumab, or a modified version thereof. In some embodiments, the antibody or antigen binding fragment thereof comprises Avelumab, Durvalumab, Atezolizumab, Sugemalimab, Sasanlimab, Envafolimab, Lodapolimab, or Cosibelimab, or a modified version thereof. In some embodiments, the antibody or antigen binding fragment thereof comprises Durvalumab. In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence of Table 1. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 1. In some embodiments, the IL-18 polypeptide of the immunocytokine provided herein comprises an amino acid sequence of any one of SEQ ID NOs: -11- 49194109.1 ES Docket No.94917-0155.737601WO 2-67. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence of SEQ ID NO: 30. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence of SEQ ID NO: 79-83. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence of SEQ ID NO: 84-86. In some embodiments, the active form of the activatable immunocytokine composition exhibits a binding affinity (KD) to at least one Fc receptor which is within 10-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. The active form of an activatable immunocytokine composition can be formed upon activation of the Act-IL-18 polypeptide comprised by the activatable immunocytokine composition, such as by cleavage at the protease cleavage site. In some embodiments, the active form of the activatable immunocytokine composition exhibits binding affinity (KD) to the antigen of the antibody which is within 5-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the active form of the activatable immunocytokine composition exhibits an ability to induce IFNγ production in a cell as measured by half-maximal effective concentration (EC50) which is within about 100-fold of the corresponding IL-18 polypeptide not comprised in the active form of the activatable immunocytokine composition, and wherein the active form of the activatable immunocytokine composition exhibits a lower EC50 than WT IL-18. In some embodiments, the active form of the activatable immunocytokine composition exhibits enhanced anti-tumor growth inhibition compared to the antibody alone. In some embodiments, the active form of the activatable immunocytokine composition exhibits enhanced anti-tumor growth inhibition compared to the antibody and the IL-18 polypeptide administered in combination. In some embodiments, the activatable immunocytokine composition provided herein, further comprises a second linker, wherein the second linker comprises a third point of attachment to the antibody or antigen binding fragment thereof, and a fourth point of attachment to an additional cytokine. In some embodiments, the additional cytokine is selected from a second IL- 18 polypeptide, an IL-7 polypeptide, or an IL-2 polypeptide. In some embodiments, the additional cytokine is a second Act-IL-18 polypeptide. In some embodiments, the second Act-IL-18 polypeptide is substantially identical to the Act-IL-18 polypeptide. In some embodiments, the third point of attachment is to a different heavy chain of the antibody or antigen binding fragment thereof from the second point of attachment. -12- 49194109.1 ES Docket No.94917-0155.737601WO In one aspect, provided herein, is a pharmaceutical composition comprising: an activatable immunocytokine composition as provided herein, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the pharmaceutical composition is formulated for parenteral or enteral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous or subcutaneous administration. In some embodiments, the pharmaceutical composition is in a lyophilized form. In some embodiments, the one or more pharmaceutically acceptable carriers or excipients comprises one or more of each of: a carbohydrate, an inorganic salt, an antioxidant, a surfactant, a buffer, or any combination thereof. In some embodiments, the pharmaceutical composition comprises one, two, three, four, five, six, seven, eight, nine, ten, or more excipients. In one aspect, provided herein, is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the activatable immunocytokine composition as provided herein, or a pharmaceutical composition as provided herein. In some embodiments, the cancer is a melanoma, a lung cancer, a bladder cancer (BC), a microsatellite instability high (MSI-H) / mismatch repair-deficient (dMMR) solid tumor, a tumor mutation burden high (TMB-H) solid tumor, a triple-negative breast cancer (TNBC), a gastric cancer (GC), a cervical cancer (CC), a pleural mesothelioma (PM), classical Hodgkin’s lymphoma (cHL), a primary mediastinal large B cell lymphoma (PMBCL), or a combination thereof. In some embodiments, the cancer is a solid cancer consisting of bladder and ureteral cancer, bone cancer, brain and spinal cord cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, eye cancer, gallbladder or bile duct cancer, germ cell tumor, head and neck cancer, kidney cancer, liver cancer, lung cancer, metastatic brain tumor, ovarian cancer, pancreatic cancer, pediatric cancer, peripheral nerve sheath tumor, pituitary cancer, prostate cancer, skin cancer, stomach or gastric cancer, soft tissue cancer, testicular cancer, thyroid cancer, uterine cancer. In some embodiments, the cancer is a carcinoma, and wherein the carcinoma comprises a cutaneous squamous cell carcinoma (CSCC), a urothelial carcinoma (UC), a renal cell carcinoma (RCC), a hepatocellular carcinoma (HCC), a head and neck squamous cell carcinoma (HNSCC), an esophageal squamous cell carcinoma (ESCC), a gastroesophageal junction (GEJ) carcinoma, an endometrial carcinoma (EC), a Merkel cell carcinoma (MCC), or a combination thereof. In some embodiments, the cancer is a leukemia, lymphoma, myeloma, or a combination thereof. In some embodiments, the cancer is leukemia and the leukemia comprises, acute lymphoblastic leukemia, -13- 49194109.1 ES Docket No.94917-0155.737601WO acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, or chronic myeloid leukemia. In some embodiments, the cancer is lymphoma and the lymphoma comprises a , BM is a blocking moiety, and wherein the orientations are shown in an N-terminal to C-terminal order, preferably wherein the Act-IL-18 polypeptide as a structure BM-CS-IL-18. In some embodiments, the blocking moiety the blocking moiety comprises an IL-18 propeptide or a portion thereof, or a variant thereof, preferably wherein the IL-18 propeptide is a human IL-18 propeptide or a variant thereof. In some embodiments, the IL-18 propeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO: 89. In some embodiments, the IL-18 propeptide comprises a substitution of the cysteine residue in SEQ ID NO: 89. In some embodiments, the IL-18 propeptide comprises the sequence set forth in SEQ ID NO: 89, 91, 96, or 97. In some embodiments, the IL- 18 polypeptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the sequence set forth in SEQ ID NO: 1. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-67 or 79-86, or another IL-18 polypeptide as described herein. In some embodiments, the specific cleavage site is comprised within a protease recognition sequence provided Table 2B. In some embodiments, the specific cleavage site is the protease recognition sequence comprises the -14- 49194109.1 ES Docket No.94917-0155.737601WO amino acid sequence set forth in any one of SEQ ID NOs: 646, 647, 648, 649, 650, 651, 652, 653, 657, 658, or 659. Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 illustrates a non-limiting mechanism of action of an activatable anti-PD-1 antibody / IL-18 wherein an activated T cell shows enhanced activation as 18 18 18 ES Docket No.94917-0155.737601WO FIG.6 shows IL-18BP inhibition of an IL-18 polypeptide of the disclosure compared to a wild type IL-18 polypeptide. FIG. 7 shows a schematic representation of coupling of a bifunctional probe to an IL-18 polypeptide provided herein. FIG. 8 shows a conditionally activatable IL-18 with terminal protease recognition sequence linked to a blocking moiety and an orthogonal conjugation handle. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG. 9 shows a conditionally activatable IL-18 polypeptide with an N-terminal protease. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG.10A shows a conditionally activatable IL-18 with a C-terminal protease recognition sequence and blocking moiety and an orthogonal conjugation handle. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG.10B shows a conditionally activatable IL-18 with a C-terminal protease recognition sequence and an orthogonal conjugation handle. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG.11 shows an illustrative example for a conditionally activatable, conjugatable IL-18 polypeptide with three N-terminal residues substituted with protease recognition sequence and blocking moiety. Upon proteolytic processing in a tumor microenvironment (TME), a functional IL-18 mutein is revealed. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG.12 shows an illustrative example for a conditionally activatable, conjugatable IL-18 polypeptide with three C-terminal residues substituted with protease recognition sequence and blocking moiety. Upon proteolytic processing in TME, a functional IL-18 mutein is revealed. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG. 13 shows an illustrative example for a conditionally activatable IL-18 polypeptide with three N-terminal residues substituted with protease recognition sequence and conjugation handle. Upon proteolytic processing in TME, free functional IL-18 mutein is revealed. Such an activatable IL-18 can be incorporated into an immunocytokine. FIG.14A shows SDS-PAGE gels showing activatable IL-18 polypeptides provided herein both before and after MMP treatment. FIG.14B shows SDS-PAGE gels showing activatable IL-18 polypeptides provided herein both before and after MMP treatment. -16- 49194109.1 ES Docket No.94917-0155.737601WO FIG.14C shows SDS-PAGE gels showing activatable IL-18 polypeptides provided herein after MMP treatment and resin purification. FT indicates flow through and E indicates eluate. FIG.14D shows a representative SDS-PAGE characterization of Act-IL-18 variants C316 and C317 described herein digested by MMP2, MMP7, MMP9, matriptase, and uPA for 48h. FIG.14E shows SDS-PAGE gels showing activatable IL-18 polypeptides provided herein both before and after MMP9 treatment. FIG.14F shows BLI characterization of Act-IL-18 variant C185 before MMP9 treatment (left) and after (right) tested against IL-18 receptor alpha subunit. 18 18 18 ES Docket No.94917-0155.737601WO FIG. 16B shows plots measuring the ability of increasing concentrations of human recombinant IL-18 binding protein (IL-18BP) to inhibit the secretion of IFNgamma by NK-92 L1 L1 an An an 18 . Fc Fc L. ES Docket No.94917-0155.737601WO FIG. 24A shows SDS-PAGE analysis of various activatable immunocytokine compositions as described herein, as well as corresponding control molecules. of on of of 92 ES Docket No.94917-0155.737601WO FIG.26B shows plots measuring the ability of the cleaved (black round symbols and solid black lines) and uncleaved (black round open symbols and dotted black lines) masked IL-18 PD- 1 immunocytokine to stimulate the secretion of IFNgamma by parental PD-1negative(left panel) and by engineered PD-1positiveNK-92 cells (right panel). The figure shows mean IFNg AlphaLISA signal on the y-axis and dosage of the masked IL-18 PD-1 immunocytokine on the x-axis. The masked IL-18 PD-1 immunocytokine tested is Composition E. FIG.26C shows plots measuring the ability of the cleaved (black round symbols and solid black lines) and uncleaved (black round open symbols and dotted black lines) masked IL-18 PD- 1 immunocytokine to stimulate the secretion of IFNgamma by parental PD-1negative(left panel) and by engineered PD-1positiveNK-92 cells (right panel). The figure shows mean IFNg AlphaLISA signal on the y-axis and dosage of the masked IL-18 PD-1 immunocytokines on the x-axis. The masked IL-18 PD-1 immunocytokines tested are Composition F and G. FIG.26D shows plots measuring the ability of the cleaved (black round symbols and solid black lines) and uncleaved (black round open symbols and dotted black lines) masked IL-18 PD- 1 immunocytokine to stimulate the secretion of IFNgamma by parental PD-1negative(left panel) and by engineered PD-1positiveNK-92 cells (right panel). The figure shows mean IFNg AlphaLISA signal on the y-axis and dosage of the masked IL-18 PD-1 immunocytokines on the x-axis. The masked IL-18 PD-1 immunocytokines tested are Composition H and I. FIG.26E shows plots measuring the ability of the cleaved (black round symbols and solid black lines) and uncleaved (black round open symbols and dotted black lines) masked IL-18 PD- 1 immunocytokine to stimulate the secretion of IFNgamma by parental PD-1negative(left panel) and by engineered PD-1positiveNK-92 cells (right panel). The figure shows mean IFNg AlphaLISA signal on the y-axis and dosage of the masked IL-18 PD-1 immunocytokines on the x-axis. The masked IL-18 PD-1 immunocytokines tested are Composition J and K. FIG.26F shows plots measuring the ability of the cleaved (black round symbols and solid black lines) and uncleaved (black round open symbols and dotted black lines) masked IL-18 PD- 1 immunocytokine to stimulate the secretion of IFNgamma by parental PD-1negative(left panel) and by engineered PD-1positiveNK-92 cells (right panel). The figure shows mean IFNg AlphaLISA signal on the y-axis and dosage of the masked IL-18 PD-1 immunocytokines on the x-axis. The masked IL-18 PD-1 immunocytokines tested are Composition L and M. -20- 49194109.1 ES Docket No.94917-0155.737601WO FIG.26G shows plots measuring the ability of the cleaved (black round symbols and solid black lines) and uncleaved (black round open symbols and dotted black lines) masked IL-18 PD- 1 18 1 18 ES Docket No.94917-0155.737601WO FIG. 27C shows plots measuring the ability of increasing concentrations of human recombinant IL-18 binding protein (IL-18BP) to inhibit the secretion of IFNgamma by parental 1 18 1 18 of R. 0. for 0 . ES Docket No.94917-0155.737601WO IFNgamma values in plasma were quantified using the Legendplex Mouse Anti-virus Response Panel according to manufacturer’s recommendations. FIG. 28E shows total drug levels (ng / mL) present in plasma on the y-axis versus time (hours after dosing) on the x-axis. Human PD1 knock-in (huPD1 ki) C57BL / 6 animals bearing sub-cutaneous MC38 tumors were treated intravenously with a single dose (SD) of 1 mg / kg on day 0 and plasma samples were harvested at different time points after dosing (n=3; Mean ± SEM). Drug in plasma was detected using a sandwich ELISA. DETAILED DESCRIPTION Disclosed herein are activatable immunocytokine compositions comprising an antibody or antigen binding fragment specific for immune cell associated antigens linked to an Act-IL-18 are In . or a In ES Docket No.94917-0155.737601WO An exemplary, non-limiting mechanism of action of an activatable immunocytokine provided herein is shown in FIG. 1. In the exemplary embodiment, the immunocytokine composition comprises an anti-PD-1 antibody as the antibody or antigen binding fragment of the activatable immunocytokine. In this embodiment, the anti-PD-1 antibody portion of the immunocytokine selectively binds to PD-1 present on the surface of an activated T cell (e.g., a CD8+T cell). This binding prevents the checkpoint interaction of PD-1 and PD-L1 / 2, thus preventing attenuation of activity of the T cell. Concomitantly, after activation of the IL-18 portion of the immunocytokine by tumor microencironment proteases, the IL-18 concentration is effectively in a high local concentration near the T-cell due to the linkage, further activates the T cell through IL-18R signaling. The activatable immunocytokine shown in this figure is depicted with two activatable IL-18 polypeptides attached to the antibody (DAR2), however activatable immunocytokines having only a single activatable IL-18 polypeptide attached (DAR1) are also expressly contemplated as within the scope of the instant disclosure. While the exemplary embodiment shows the mechanism of action of an anti-PD-1 antibody, antibodies or antigen binding fragments specific for other immune antigens provided herein can function according to a similar mechanism. Another exemplary, non-limiting mechanism of action of an anti-PD-L1 antibody / IL-18 activatable immunocytokine is shown in FIG. 17A. In the exemplary embodiment, the anti-PD- L1 antibody portion of the immunocytokine binds to PD-L1 expressed on the surface of a tumor cell. When a T cell comes into contact with the tumor cell, an interaction between PD-1 on the T cell and PD-L1 on the cell is blocked, preventing attenuation of the activity of the T cell. Additionally, the IL-18 portion of the immunocytokine, upon cleavage by tumor proteases to activate the IL-18 polypeptide, signals through IL-18R on the immune cell, thereby inducing production of IFNγ and further activation of the immune cell. Though this exemplary embodiment is demonstrated for PD-L1, other immune antigens provided herein in immunocytokines may display similar mechanisms of action. Analogously, FIG. 17B illustrates a non-limiting mechanism of action of an anti-PD-L1 antibody / IL-18 activatable immunocytokine acting on an immune cell expressing both IL-18R and PD-L1. FIG. 18 illustrates an immunocytokine composition provided herein with two different protein payloads (e.g., IL-18 and IL-2) linked to an antibody (e.g., PD-L1 antibody) acting on an immune cell with simultaneous activation of two -24- 49194109.1 ES Docket No.94917-0155.737601WO different receptors (e.g., IL-18R and IL-2R). One of the protein payloads can be an activatable IL- 18 polypeptide as provided herein. Also disclosed herein are methods of manufacturing the activatable immunocytokines provided herein. In some embodiments, the activatable immunocytokine compositions are prepared using chemical linkers which can attach the two moieties of immunocytokine composition to each other at pre-selected sites of each moiety with high fidelity. In some embodiments, the methods provided herein can be used on a wide variety of antibodies or antigen binding fragments in order to rapidly and easily generate a wide variety of immune antigen specific antibody or antigen binding fragments linked to activatable IL-18 polypeptides as immunocytokines. In some embodiments, the methods can be used on readily commercially available antibodies to allow for rapid linking with Act-IL-18 polypeptides provided herein. One non-limiting illustration of an immunocytokine as provided herein is shown in FIG. 19, which depicts an IL-18 polypeptide linked to an antibody as provided herein with a point of attachment of the linker to the IL-18 polypeptide at a side chain of a residue and to a side chain of a residue in the Fc region. The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope. Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Immune Antigen Specific Antibodies Linked to Act-IL-18 Polypeptides as activatable Immunocytokines Provided herein are antibodies and antigen binding fragments which bind to immune cell associated antigens, linked to Act-IL-18 polypeptides as activatable immunocytokine compositions. The activatable immunocytokine compositions provided herein are effective for -25- 49194109.1 ES Docket No.94917-0155.737601WO simultaneously delivering the IL-18 polypeptide and the antibody or antigen binding fragment to a target cell, such as an immune cell. This simultaneous delivery of both agents to the same cell has numerous benefits, including improved IL-18 polypeptide selectivity, enhanced therapeutic potential of the IL-18 polypeptide, and minimized risk of side effects from administering IL-18 therapies. In some embodiments, the activatable immunocytokine compositions act through multiple modes of action, including without limitation disrupting an activity of the immune cell associated antigen (e.g., immune checkpoint evasion) and / or enhanced activation of immune cells in or around a tumor microenvironment. The activatable immunocytokine compositions provided herein utilize linkers to attach the antibody or antigen binding fragment to the Act-IL-18 polypeptide. In some embodiments, the linkers are attached to each moiety (i.e., the antibody or antigen binding fragment and the IL-18 polypeptide) at specific residues or a specific subset of residues. In some embodiments, the linkers are attached to each moiety in a site-selective manner, such that a population of the activatable immunocytokine compositions is substantially uniform. This can be accomplished in a variety of ways as provided herein, including by site-selectively adding reagents for a conjugation reaction to a moiety to be conjugated, synthesizing or otherwise preparing a moiety to be conjugated with a desired reagent for a conjugation reaction, or a combination of these two approaches. Using these approaches, the sites of attachment (such as specific amino acid residues) of the linker to each moiety can be selected with precision. Additionally, these approaches allow a variety of linkers to be employed for the composition which are not limited to amino acid residues as is required for fusion proteins. This combination of linker choice and precision attachment to the moieties allows the linker to also, in some embodiments, perform the function of modulating the activity of one of the moieties, for example if the linker is attached to the Act-IL-18 polypeptide at a position that interacts with a protein which binds to the IL-18 polypeptide (e.g., IL-18 binding protein). In one aspect, provided herein, is an activatable immunocytokine composition, comprising: an Act-IL-18 polypeptide and an antibody or an antigen binding fragment thereof specific for an immune cell associated antigen. In some embodiments, the activatable immunocytokine composition comprises a linker. In some embodiments, the linker comprises a first point of attachment to the antibody or antigen binding fragment thereof. In some embodiments, the linker comprises a second point of attachment to the IL-18 polypeptide. -26- 49194109.1 ES Docket No.94917-0155.737601WO The present disclosure describes antibodies or antigen binding fragments linked to Act-IL- 18 polypeptides as activatable immunocytokine compositions and their use as therapeutic agents. is is is production, and inhibition of IL-18 activity by IL-18BP. IL-18 induces IFNγ production, which in turn induces IL-18BP production. IL-18BP then competes with IL-18Rα to inhibit IL-18 activity. In some embodiments, the IL-18 polypeptides of the activatable immunocytokines provided herein display reduced binding to IL-18BP and retain binding to the IL-18 receptor. The IL-18 polypeptides with this property provided herein are able to retain IL-18 receptor signaling activity (including inducing production of IFNγ) even in the presence of IL-18BP. This allows the immunocytokines provided herein to retain IL-18 signaling activity well beyond a short period of time after administration, or upon repeat administrations. In some embodiments, the modified IL- 18 polypeptides with this property comprise a modification (e.g., substitution, polymer attachment, or deletion) at one or more amino acid residues which convey this property to the IL-18 -27- 49194109.1 ES Docket No.94917-0155.737601WO polypeptide. Examples of IL-18 polypeptides with this property are provided herein, as well as those otherwise known, such as those described in Patent Cooperation Treaty Publication Nos. WO2019051015, WO2022094473, WO2022172944, WO2022172944, WO2022172944, WO2022172944, and WO2022172944. In addition to IL-18 polypeptides provided herein, these otherwise known IL-18 polypeptides or their analogs may similarly be modified with points of attachment to the linker as provided herein, or, in some instances, combined with artificial peptides as described herein. Immune Cell Specific Antibodies In some embodiments, an antibody or an antigen binding fragment of an activatable immunocytokine of the disclosure specifically binds to an immune cell associated antigen. An immune cell associated antigen provided herein is an antigen which is associated with expression on immune cells or associated with activity of immune cells (e.g., an antigen associated with immune cell activation or deactivation), or both. In some embodiments, the immune cell associated antigen is expressed at a level of at least 25% greater, at least 30% greater, at least 40% greater, at least 50% greater, at least 60% greater, at least 70% greater, at least 80% greater, at least 90% greater, or at least 100% greater in the immune cell than another cell. In some embodiments, the immune cell associated antigen is expressed at a level of at least 2-fold greater, at least 4-fold greater, at least 6-fold greater, at least 8-fold greater, or at least 10-fold greater in the immune cell than another cell. Non-limiting examples of immune cell associated antigens include 4-IBB, CD3, CCR8, CD8A, CD8B, CD16A, CD28, CD80, CD86, CD96, CD226, CTLA-4, D40, GITR, ICOS, LAG-3, MHCI, MHCII, NKG2A, NKG2D, NKp30, NKp44, NKp46, OX40, PD-1, PD-L1, PD- L2, SIRPA, TCR, TIGIT, TIM-3, and VISTA. An antibody selectively binds or preferentially binds to a target if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to specific binding means preferential binding where the affinity of the antibody, or antigen binding fragment thereof, is at least at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, at least 10- fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50- -28- 49194109.1 ES Docket No.94917-0155.737601WO fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90- fold greater, at least 100-fold greater, or at least 1000-fold greater than the affinity of the antibody for unrelated amino acid sequences. In some embodiments, an antibody or an antigen binding fragment of the disclosure can inhibit the action / activity of the substance to which it binds. In some embodiments, an antibody or antigen binding fragment of the disclosure can agonize the action / activity of the substance to which it binds (e.g., an immune cell agonist antibody or antigen binding fragment such as one specific for CD16A, NKG2D, NKp30, or other targets). As used herein, the term “antibody” refers to an immunoglobulin (Ig), polypeptide, or a protein having a binding domain which is, or is homologous to, an antigen binding domain. The term further includes “antigen binding fragments” and other interchangeable terms for similar binding fragments as described below. Native antibodies and native immunoglobulins (Igs) are generally heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light chains and two identical heavy chains. Each light chain is typically linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (“VH”) followed by a number of constant domains (“CH”). Each light chain has a variable domain at one end (“VL”) and a constant domain (“CL”) at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains. In some instances, an antibody or an antigen binding fragment comprises an isolated antibody or antigen binding fragment, a purified antibody or antigen binding fragment, a recombinant antibody or antigen binding fragment, a modified antibody or antigen binding fragment, or a synthetic antibody or antigen binding fragment. Antibodies and antigen binding fragments herein can be partly or wholly synthetically produced. An antibody or antigen binding fragment can be a polypeptide or protein having a binding domain which can be, or can be homologous to, an antigen binding domain. In one instance, an antibody or an antigen binding fragment can be produced in an appropriate in vivo animal model and then isolated and / or purified. -29- 49194109.1 ES Docket No.94917-0155.737601WO Depending on the amino acid sequence of the constant domain of its heavy chains, immunoglobulins (Igs) can be assigned to different classes. There are five major classes of or is an be on by ES Docket No.94917-0155.737601WO (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., 1991, National Institutes of Health, Bethesda Md., pages 647-669; hereafter “Kabat”); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-Iazikani et al. (1997) J. Molec. Biol. 273:927-948). As used herein, a CDR may refer to CDRs defined by either approach or by a combination of both approaches. With respect to antibodies, the term “variable domain” refers to the variable domains of antibodies that are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. Rather, it is concentrated in three segments called hypervariable regions (also known as CDRs) in both the light chain and the heavy chain variable domains. More highly conserved portions of variable domains are called the “framework regions” or “FRs.” The variable domains of unmodified heavy and light chains each contain four FRs (FR1, FR2, FR3, and FR4), largely adopting a β-sheet configuration interspersed with three CDRs which form loops connecting and, in some cases, part of the β-sheet structure. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies (see, Kabat). The terms “hypervariable region” and “CDR” when used herein, refer to the amino acid residues of an antibody which are responsible for antigen binding. The CDRs comprise amino acid residues from three sequence regions which bind in a complementary manner to an antigen and are known as CDR1, CDR2, and CDR3 for each of the VH and VL chains. In the light chain variable domain, the CDRs typically correspond to approximately residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3), and in the heavy chain variable domain the CDRs typically correspond to approximately residues 31-35 (CDRH1), 50-65 (CDRH2), and 95-102 (CDRH3) according to Kabat et al., Id. It is understood that the CDRs of different antibodies may contain insertions, thus the amino acid numbering may differ. The Kabat numbering system accounts for such insertions with a numbering scheme that utilizes letters attached to specific residues (e.g., 27A, 27B, 27C, 27D, 27E, and 27F of CDRL1 in the light chain) to reflect any insertions in the numberings between different antibodies. Alternatively, in the light chain variable domain, the CDRs typically correspond to approximately residues 26-32 (CDRL1), 50-52 (CDRL2), and 91- 96 (CDRL3), and in the heavy chain variable domain, the CDRs typically correspond to -31- 49194109.1 ES Docket No.94917-0155.737601WO approximately residues 26-32 (CDRH1), 53-55 (CDRH2), and 96-101 (CDRH3) according to Chothia and Lesk (J. Mol. Biol., 196: 901-917 (1987)). As used herein, “framework region,” “FW,” or “FR” refers to framework amino acid residues that form a part of the antigen binding pocket or groove. In some embodiments, the framework residues form a loop that is a part of the antigen binding pocket or groove and the amino acids residues in the loop may or may not contact the antigen. Framework regions generally comprise the regions between the CDRs. In the light chain variable domain, the FRs typically correspond to approximately residues 0-23 (FRL1), 35-49 (FRL2), 57-88 (FRL3), and 98-109 and in the heavy chain variable domain the FRs typically correspond to approximately residues 0-30 (FRH1), 36-49 (FRH2), 66-94 (FRH3), and 103-133 according to Kabat et al., Id. As discussed above with the Kabat numbering for the light chain, the heavy chain too accounts for insertions in a similar manner (e.g., 35A, 35B of CDRH1 in the heavy chain). Alternatively, in the light chain variable domain, the FRs typically correspond to approximately residues 0-25 (FRL1), 33-49 (FRL2) 53-90 (FRL3), and 97-109 (FRL4), and in the heavy chain variable domain, the FRs typically correspond to approximately residues 0-25 (FRH1), 33-52 (FRH2), 56-95 (FRH3), and 102-113 (FRH4) according to Chothia and Lesk, Id. The loop amino acids of a FR can be assessed and determined by inspection of the three-dimensional structure of an antibody heavy chain and / or antibody light chain. The three-dimensional structure can be analyzed for solvent accessible amino acid positions as such positions are likely to form a loop and / or provide antigen contact in an antibody variable domain. Some of the solvent accessible positions can tolerate amino acid sequence diversity and others (e.g., structural positions) are, generally, less diversified. The three- dimensional structure of the antibody variable domain can be derived from a crystal structure or protein modeling. In the present disclosure, the following abbreviations (in the parentheses) are used in accordance with the customs, as necessary: heavy chain (H chain), light chain (L chain), heavy chain variable region (VH), light chain variable region (VL), complementarity determining region (CDR), first complementarity determining region (CDR1), second complementarity determining region (CDR2), third complementarity determining region (CDR3), heavy chain first complementarity determining region (VH CDR1), heavy chain second complementarity determining region (VH CDR2), heavy chain third complementarity determining region (VH CDR3), light chain first complementarity determining region (VL CDR1), light chain second -32- 49194109.1 ES Docket No.94917-0155.737601WO complementarity determining region (VL CDR2), and light chain third complementarity determining region (VL CDR3). The term “Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain. The “Fc region” may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is generally defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The numbering of the residues in the Fc region is that of the EU index as in Kabat. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3. “Antibodies” useful in the present disclosure encompass, but are not limited to, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, bispecific antibodies, grafted antibodies, multispecific antibodies, heteroconjugate antibodies, humanized antibodies, human antibodies, deimmunized antibodies, mutants thereof, fusions thereof, immunoconjugates thereof, antigen binding fragments thereof, and / or any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. In certain embodiments of the methods and conjugates provided herein, the antibody requires an Fc region to enable attachment of a linker between the antibody and the protein (e.g., attachment of the linker using an affinity peptide, such as in AJICAPTMtechnology). In some instances, an antibody is a monoclonal antibody. As used herein, a “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen (epitope). The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. In some instances, an antibody is a humanized antibody. As used herein, “humanized” antibodies refer to forms of non-human (e.g., murine) antibodies that are specific chimeric immunoglobulins, immunoglobulin chains, or fragments thereof that contain minimal sequence -33- 49194109.1 ES Docket No.94917-0155.737601WO derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity determining or In at or for of ES Docket No.94917-0155.737601WO acid spanning the test antibody variable region sequence. Each 9mer peptide can be tested against each of the 34 MHC class II allotypes and scored based on their potential “fit” and interactions in the so an B ES Docket No.94917-0155.737601WO bispecific molecule, facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations. According to one approach to making bispecific antibodies, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. The fusion can be with an immunoglobulin heavy chain constant domain, comprising at least part of the hinge, CH2 and CH3 regions. The first heavy chain constant region (CH1), containing the site necessary for light chain binding, can be present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co- transfected into a suitable host organism. This provides for great flexibility in adjusting the mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yields. It is, however, possible to insert the coding sequences for two or all three polypeptide chains in one expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios are of no particular significance. In some instances, an antibody herein is a chimeric antibody. “Chimeric” forms of non- human (e.g., murine) antibodies include chimeric antibodies which contain minimal sequence derived from a non-human Ig. For the most part, chimeric antibodies are murine antibodies in which at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, is inserted in place of the murine Fc. Chimeric or hybrid antibodies also may be prepared in vitro using suitable methods of synthetic protein chemistry, including those involving cross-linking agents. Provided herein are antibodies and antigen binding fragments thereof, modified antibodies and antigen binding fragments thereof, and binding agents that specifically bind to one or more epitopes on one or more target antigens. In one instance, a binding agent selectively binds to an epitope on a single antigen. In another instance, a binding agent is bivalent and either selectively binds to two distinct epitopes on a single antigen or binds to two distinct epitopes on two distinct antigens. In another instance, a binding agent is multivalent (i.e., trivalent, quatravalent, etc.) and the binding agent binds to three or more distinct epitopes on a single antigen or binds to three or more distinct epitopes on two or more (multiple) antigens. -36- 49194109.1 ES Docket No.94917-0155.737601WO Antigen binding fragments of any of the antibodies herein are also contemplated. The terms “antigen binding portion of an antibody,” “antigen binding domain,” “antibody fragment,” or a “functional fragment of an antibody” are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. Representative antigen binding fragments include, but are not limited to, a Fab, a Fab', a F(ab')2, a bispecific F(ab')2, a trispecific F(ab')2, a variable fragment (Fv), a single chain variable fragment (scFv), a dsFv, a bispecific scFv, a variable heavy domain, a variable light domain, a variable NAR domain, bispecific scFv, an AVIMER®, a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a minibody, a maxibody, a camelid, a VHH, a minibody, an intrabody, fusion proteins comprising an antibody portion (e.g., a domain antibody), a single chain binding polypeptide, a scFv-Fc, a Fab-Fc, a bispecific T cell engager (BiTE; two scFvs produced as a single polypeptide chain, where each scFv comprises an amino acid sequences a combination of CDRs or a combination of VL / VL described herein), a tetravalent tandem diabody (TandAb; an antibody fragment that is produced as a non-covalent homodimer folder in a head-to-tail arrangement, e.g., a TandAb comprising an scFv, where the scFv comprises an amino acid sequences a combination of CDRs or a combination of VL / VL described herein), a Dual-Affinity Re-targeting Antibody (DART; different scFvs joined by a stabilizing interchain disulphide bond), a bispecific antibody (bscAb; two single-chain Fv fragments joined via a glycine-serine linker), a single domain antibody (sdAb), a fusion protein, a bispecific disulfide-stabilized Fv antibody fragment (dsFv–dsFv′; two different disulfide- stabilized Fv antibody fragments connected by flexible linker peptides). In certain embodiments of the invention, a full length antibody (e.g., an antigen binding fragment and an Fc region) is preferred. Heteroconjugate polypeptides comprising two covalently joined antibodies or antigen binding fragments of antibodies are also within the scope of the disclosure. Suitable linkers may be used to multimerize binding agents. Non-limiting examples of linking peptides include, but are not limited to, (GS)n (SEQ ID NO: 424), (GGS)n (SEQ ID NO: 425), (GGGS)n (SEQ ID NO: 426), (GGSG)n (SEQ ID NO: 427), or (GGSGG)n (SEQ ID NO: 428), (GGGGS)n (SEQ ID NO: 429), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For example, a linking peptide can be (GGGGS)3 (SEQ ID NO: 430) or (GGGGS)4 (SEQ ID NO: 431). In some embodiments, a linking peptide bridges approximately 3.5 nm between the carboxy terminus of one variable region and the amino terminus of the other variable region. Linkers of other sequences have been designed and used. Linkers can -37- 49194109.1 ES Docket No.94917-0155.737601WO in turn be modified for additional functions, such as attachment of drugs or attachment to solid supports. As used herein, the term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution. Apparent affinities can be determined by methods such as an enzyme-linked immunosorbent assay (ELISA) or any other suitable technique. Avidities can be determined by methods such as a Scatchard analysis or any other suitable technique. As used herein, the term “affinity” refers to the equilibrium constant for the reversible binding of two agents and is expressed as KD. The binding affinity (KD) of an antibody or antigen binding fragment herein can be less than 500 nM, 475 nM, 450 nM, 425 nM, 400 nM, 375 nM, 350 nM, 325 nM, 300 nM, 275 nM, 250 nM, 225 nM, 200 nM, 175 nM, 150 nM, 125 nM, 100 nM, 90 nM, 80 nM, 70 nM, 50 nM, 50 nM, 49 nM, 48 nM, 47 nM, 46 nM, 45 nM, 44 nM, 43 nM, 42 nM, 41 nM, 40 nM, 39 nM, 38 nM, 37 nM, 36 nM, 35 nM, 34 nM, 33 nM, 32 nM, 31 nM, 30 nM, 29 nM, 28 nM, 27 nM, 26 nM, 25 nM, 24 nM, 23 nM, 22 nM, 21 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920 pM, be ES Docket No.94917-0155.737601WO mutagenesis works as follows. One or more amino acid position in the CDR is replaced with two or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acids. This are or or a an is ES Docket No.94917-0155.737601WO embodiments, the immune cell associated antigen is associated with a T cell, a monocyte, and / or a natural killer (NK) cell. In embodiments, the immune cell antigen is associated with a T cell. In some embodiments, the immune cell antigen is associated with an effector T cell, a cytotoxic T cell, a helper T cell, a regulatory T cell, and / or a memory T cell. In some embodiments, the immune cell associated antigen is an immune checkpoint molecule. In some embodiments, the immune cell associated antigen is a costimulatory antigen. In some embodiments, the immune cell associated antigen is an macrophage cell surface antigen. In some embodiments, the immune cell associated antigen is an NK cell surface antigen. In some embodiments, the immune cell associated antigen is a T cell surface antigen (e.g., CD8A, CD8B). In some embodiments, the immune cell associated antigen is 4-IBB, B7-H3, B7-H4, BTLA, CD3, CCR8, CD8A, CD8B, CD16A, CD27, CD28, CD33, CD38, CD39, CD40, CD47, CD70, CD80, CD86, CD96, CD163, CLEC-1, CLEVER-1, CTLA-4, D40, GITR, ICOS, ILT2 / 3 / 4, LAG-3, MHCI, MHCII, NKG2A, NKG2D, NKp30, NKp44, NKp46, OX40, PD-1, PD- L1, PD-L2, PSGL-1, SIGLEC-9, SIGLEC-15, SIRP-α, TCR,TIGIT, TIM-3,VISTA, or VSIG4.. In some embodiments, the immune cell associated antigen is PD-1. In some embodiments, the immune cell associated antigen is CCR8, CD8A, CD8B, CD16A, CD96, CD226, CTLA-4, ICOS, LAG-3, NKG2A, NKG2D, NKp30, NKp44, NKp46, PD-1, PD-L1, TIGIT, or TIM-3. In some embodiments, the immune cell associated antigen is 4-1BB. In some embodiments, the immune cell associated antigen is B7-H3. In some embodiments, the immune cell associated antigen is B7-H4. In some embodiments, the immune cell associated antigen is BTLA. In some embodiments, the immune cell associated antigen is CD3. In some embodiments, the immune cell associated antigen is CCR8. In some embodiments, the immune cell associated antigen is CD8A. In some embodiments, the immune cell associated antigen is CD8B. In some embodiments, the immune cell associated antigen is CD16A. In some embodiments, the immune cell associated antigen is CD27. In some embodiments, the immune cell associated antigen is CD33. In some embodiments, the immune cell associated antigen is CD38. In some embodiments, the immune cell associated antigen is CD39. In some embodiments, the immune cell associated antigen is CD40. In some embodiments, the immune cell associated antigen is CD47. In some embodiments, the immune cell associated antigen is CD80. In some embodiments, the immune cell associated antigen is CD86. In some embodiments, the immune cell associated antigen is CD96. In some embodiments, the immune cell associated antigen is CD163. In some embodiments, the immune -40- 49194109.1 ES Docket No.94917-0155.737601WO cell associated antigen is CLEC-1. In some embodiments, the immune cell associated antigen is CLEVER-1. In some embodiments, the immune cell associated antigen is CTLA4. In some embodiments, the immune cell associated antigen is D40. In some embodiments, the immune cell associated antigen is GITR. In some embodiments, the immune cell associated antigen is ICOS. In some embodiments, the immune cell associated antigen is ILT2 / 3 / 4. In some embodiments, the immune cell associated antigen is LAG-3. In some embodiments, the immune cell associated antigen is MHCI. In some embodiments, the immune cell associated antigen is MHCII. In some embodiments, the immune cell associated antigen is NKG2A. In some embodiments, the immune cell associated antigen is NKp30. In some embodiments, the immune cell associated antigen is NKp44. In some embodiments, the immune cell associated antigen is NKp46. In some embodiments, the immune cell associated antigen is OX40. In some embodiments, the immune cell associated antigen is PD-1. In some embodiments, the immune cell associated antigen is PD- L1. In some embodiments, the immune cell associated antigen is PD-L2. In some embodiments, the immune cell associated antigen is PSGL-1. In some embodiments, the immune cell associated antigen is SIGLEC-9. In some embodiments, the immune cell associated antigen is SIGLEC-15. In some embodiments, the immune cell associated antigen is SIRP-α. In some embodiments, the immune cell associated antigen is TCR. In some embodiments, the immune cell associated antigen is TIGIT. In some embodiments, the immune cell associated antigen is TIM-3. In some embodiments, the immune cell associated antigen is VISTA. In some embodiments, the immune cell associated antigen is VSIG4. In some embodiments, the antibody or antigen binding fragment thereof is an anti-PD-1 antibody or antigen binding fragment. Programmed cell death protein 1 (also known as PD-1 and CD279), is a cell surface receptor that plays an role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1 is an immune cell inhibitory molecule that is expressed on activated B cells, T cells, and myeloid cells. PD-1 represents an immune checkpoint and guards against autoimmunity via a dual mechanism of promoting apoptosis (programmed cell death) in antigen-specific T-cells in lymph nodes while reducing apoptosis in regulatory T cells. PD-1 is a member of the CD28 / CTLA-4 / ICOS costimulatory receptor family that delivers negative signals that affect T and B cell immunity. PD- 1 is monomeric both in solution as well as on cell surface, in contrast to CTLA-4 and other family members that are all disulfide-linked homodimers. Signaling through the PD-1 inhibitory receptor -41- 49194109.1 ES Docket No.94917-0155.737601WO upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays a role in the maintenance of peripheral immune tolerance. The interaction between PD- 1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T cell receptor mediated proliferation, and immune evasion by the cancerous cells. A non-limiting, exemplary, human PD-1 amino acid sequence is MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSN TSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRN DSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGG LLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTP EPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL (SEQ ID NO: 331). In one embodiment, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment of the disclosure comprises a combination of a heavy chain variable region (VH) and a light chain variable region (VL) described herein. In another embodiment, an anti-PD-1 antibody or an anti- PD-1 antigen binding fragment of the disclosure comprises a combination of complementarity determining regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) described herein. In one embodiment, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment of the disclosure comprises a modified Tislelizumab, Baizean, 0KVO411B3N, BGB- A317, hu317-1 / IgG4mt2, Sintilimab, Tyvyt, IBI-308, Toripalimab, TeRuiPuLi, Terepril, Tuoyi, JS-001, TAB-001, Camrelizumab, HR-301210, INCSHR-01210, SHR-1210, Cemiplimab, Cemiplimab-rwlc, LIBTAYO®, 6QVL057INT, H4H7798N, REGN-2810, SAR-439684, Avelumab, BAVENCIO®, 451238, KXG2PJ551I, MSB-0010682, MSB-0010718C, PF-06834635, Durvalumab, IMFINZI®, 28X28X9OKV, MEDI-4736, Lambrolizumab, Pembrolizumab, KEYTRUDA®, MK-3475, SCH-900475, h409A11, Nivolumab, Nivolumab BMS, OPDIVO®, BMS-936558, MDX-1106, ONO-4538, Prolgolimab, Forteca, BCD-100, Penpulimab, AK-105, Zimberelimab, AB-122, GLS-010, WBP-3055, Balstilimab, 1Q2QT5M7EO, AGEN-2034, AGEN-2034w, Genolimzumab, Geptanolimab, APL-501, CBT-501, GB-226, Dostarlimab, ANB- 011, GSK-4057190A, P0GVQ9A4S5, TSR-042, WBP-285, Serplulimab, HLX-10, CS-1003, Retifanlimab, 2Y3T5IF01Z, INCMGA-00012, INCMGA-0012, MGA-012, Sasanlimab, LZZ0IC2EWP, PF-06801591, RN-888, Spartalizumab, NVP-LZV-184, PDR-001, QOG25L6Z8Z, Relatlimab / nivolumab, BMS-986213, Cetrelimab, JNJ-3283, JNJ-63723283, -42- 49194109.1 ES Docket No.94917-0155.737601WO LYK98WP91F, Tebotelimab, MGD-013, BCD-217, BAT-1306, HX-008, MEDI-5752, JTX- 4014, Cadonilimab, AK-104, BI-754091, Pidilizumab, CT-011, MDV-9300, YBL-006, AMG- 256, RG-6279, RO-7284755, BH-2950, IBI-315, RG-6139, RO-7247669, ONO-4685, AK-112, 609-A, LY-3434172, T-3011, MAX-10181, AMG-404, IBI-318, MGD-019, INCB-086550, ONCR-177, LY-3462817, RG-7769, RO-7121661, F-520, XmAb-23104, Pd-1-pik, SG-001, S- 95016, Sym-021, LZM-009, Budigalimab, 6VDO4TY3OO, ABBV-181, PR-1648817, CC-90006, XmAb-20717, 2661380, AMP-224, B7-DCIg, EMB-02, ANB-030, PRS-332, [89Zr]Deferoxamide-pembrolizumab, 89Zr-Df-Pembrolizumab, [89Zr]Df-Pembrolizumab, STI- 1110, STI-A1110, CX-188, mPD-1 Pb-Tx, MCLA-134, 244C8, ENUM 224C8, ENUM C8, 388D4, ENUM 388D4, ENUM D4, MEDI0680, or AMP-514. In some embodiments, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment of the disclosure comprises a Tislelizumab, Sintilimab, Toripalimab, Terepril, Camrelizumab, Cemiplimab, Pembrolizumab Nivolumab, Prolgolimab, Penpulimab, Zimberelimab, Balstilimab, Genolimzumab, Geptanolimab, Dostarlimab, Serplulimab, Retifanlimab, Sasanlimab, Spartalizumab, Cetrelimab, Tebotelimab, Cadonilimab, A Pidilizumab, LZM-009, or Budigalimab. In one embodiment, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment of the disclosure comprises a modified Tislelizumab, Sintilimab, Toripalimab, Terepril, Camrelizumab, Cemiplimab, Pembrolizumab Nivolumab, Prolgolimab, Penpulimab, Zimberelimab, Balstilimab, Genolimzumab, Geptanolimab, Dostarlimab, Serplulimab, Retifanlimab, Sasanlimab, Spartalizumab, Cetrelimab, Tebotelimab, Cadonilimab, Pidilizumab, LZM-009, or Budigalimab. In some embodiments, the anti-PD-1 polypeptide is Nivolumab, Pembrolizumab, LZM- 009, Dostarlimab, Sintilimab, Spartalizumab, Tislelizumab, or Cemiplimab. In some embodiment, the anti-PD-1 polypeptide is Dostarlimab, Sintilimab, Spartalizumab, or Tislelizumab. In some embodiments, the anti-PD-1 polypeptide is Nivolumab, Pembrolizumab, LZM-009, or Cemiplimab. In some embodiments, the anti-PD-1 polypeptide is LZM-009. The VH and VL of LZM- 009 are provided in Table 1 below as SEQ ID NOs: 376 and 377, respectively. The full length heavy chain of LZM-009 has the sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMYWVRQAPGQGLEWMGGVNPSNG GTNFNEKFKSRVTITADKSTSTAYMELSSLRSEDTAVYYCARRDYRYDMGFDYWGQGT -43- 49194109.1 ES Docket No.94917-0155.737601WO TVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 404). The full length light chain of LZM-009 has the sequence EIVLTQSPATLSLSPGERATISCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG VPARFSGSGSGTDFTLTISSLEPEDFATYYCQHSRELPLTFGTGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 405). In some embodiments, the anti-PD-1 antibody is Pembrolizumab. In some embodiments, the anti-PD-1 antibody is modified Pembrolizumab. In some embodiments, the anti-PD-1 antibody is a biosimilar of Tislelizumab, Sintilimab, Toripalimab, Terepril, Camrelizumab, Cemiplimab, Pembrolizumab Nivolumab, Prolgolimab, Penpulimab, Zimberelimab, Balstilimab, Genolimzumab, Geptanolimab, Dostarlimab, Serplulimab, Retifanlimab, Sasanlimab, Spartalizumab, Cetrelimab, Tebotelimab, Cadonilimab, A Pidilizumab, LZM-009, or Budigalimab. In some embodiments, the anti-PD-1 antibody is a biosimilar of any one of the antibodies provided herein. TABLE 1 provides the sequences of exemplary anti-PD-1 antibodies and anti-PD-1 antigen binding fragments that can be modified to prepare anti-PD-1 immunoconjugates. TABLE 1 also shows provides combinations of CDRs that can be utilized in a modified anti-PD-1 immunoconjugate. Reference to an anti-PD-1 antibody herein may alternatively refer to an anti- PD-1 antigen binding fragment. In some instances, the SEQ ID NOs listed in Table 1 contain full-length heavy or light chains of the indicated antibodies with the VH or VL respectively indicated in bold. Where there is a reference herein to a VH or VL of a SEQ ID NO in Table 1 which contains a full-length heavy or light chain, it is intended to reference the bolded portion of the sequence. For example, reference to “a VH having an amino acid sequence shown in SEQ ID NO: 332” refers to the bolded portion of SEQ ID NO: 332 in Table 1. -44- 49194109.1 ES Docket No.94917-0155.737601WO An anti-PD-1 antibody or an anti-PD-1 antigen binding fragment can comprise a VH having an amino acid sequence of any one of SEQ ID NOS: 332, 334, 336, 338, 340, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, and 378. An anti-PD-1 antibody or an anti-PD-1 antigen binding fragment can comprise a VL having an amino acid sequence of any one of SEQ ID NOS: 333, 335, 337, 339, 341, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, and 379. An anti-PD-1 antibody or an anti-PD-1 antigen binding fragment can comprise a heavy chain or VH having an amino acid sequence of any one of SEQ ID NOS: 332, 334, 336, 338, 340, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, and 378, or a portion corresponding to a VH thereof. An anti-PD-1 antibody or an anti-PD-1 antigen binding fragment can comprise a light chain or VL having an amino acid sequence of any one of SEQ ID NOS: 333, 335, 337, 339, 341, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, and 379, or a portion corresponding to a VL thereof. In one instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 332, and a VL having an amino acid sequence shown in SEQ ID NO: 333. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 334, and a VL having an amino acid sequence shown in SEQ ID NO: 335. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 336, and a VL having an amino acid sequence shown in SEQ ID NO: 337. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 338, and a VL having an amino acid sequence shown in SEQ ID NO: 339. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 340, and a VL having an amino acid sequence shown in SEQ ID NO: 341. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 346, and a VL having an amino acid sequence shown in SEQ ID NO: 347. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 348, and a VL having an amino acid sequence shown in SEQ ID NO: 349. In another instance, an anti-PD- 1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid -45- 49194109.1 ES Docket No.94917-0155.737601WO sequence shown in SEQ ID NO: 350, and a VL having an amino acid sequence shown in SEQ ID NO: 351. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 352, and a VL having an amino acid sequence shown in SEQ ID NO: 353. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 354, and a VL having an amino acid sequence shown in SEQ ID NO: 355. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 356, and a VL having an amino acid sequence shown in SEQ ID NO: 357. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 358, and a VL having an amino acid sequence shown in SEQ ID NO: 359. In another instance, an anti-PD- 1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 360, and a VL having an amino acid sequence shown in SEQ ID NO: 361. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 362, and a VL having an amino acid sequence shown in SEQ ID NO: 363. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 364, and a VL having an amino acid sequence shown in SEQ ID NO: 365. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 366, and a VL having an amino acid sequence shown in SEQ ID NO: 367. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 368, and a VL having an amino acid sequence shown in SEQ ID NO: 369. In another instance, an anti-PD- 1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 370, and a VL having an amino acid sequence shown in SEQ ID NO: 371. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 372, and a VL having an amino acid sequence shown in SEQ ID NO: 373. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 374, and a VL having an amino acid sequence shown in SEQ ID NO: 375. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having -46- 49194109.1 ES Docket No.94917-0155.737601WO an amino acid sequence shown in SEQ ID NO: 376, and a VL having an amino acid sequence shown in SEQ ID NO: 377. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 378, and a VL having an amino acid sequence shown in SEQ ID NO: 379. In one instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 332, and a VL having an amino acid sequence of SEQ ID NO: 333. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 334, and a VL having an amino acid sequence of SEQ ID NO: 335. In another instance, an anti-PD-1 antibody or an anti- PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 336, and a VL having an amino acid sequence of SEQ ID NO: 337. In another instance, an anti- PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 338, and a VL having an amino acid sequence of SEQ ID NO: 339. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 340, and a VL having an amino acid sequence of SEQ ID NO: 341. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 346, and a VL having an amino acid sequence of SEQ ID NO: 347. In another instance, an anti-PD-1 antibody or an anti- PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 348, and a VL having an amino acid sequence of SEQ ID NO: 349. In another instance, an anti- PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 350, and a VL having an amino acid sequence of SEQ ID NO: 351. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 352, and a VL having an amino acid sequence of SEQ ID NO: 353. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 354, and a VL having an amino acid sequence of SEQ ID NO: 355. In another instance, an anti-PD-1 antibody or an anti- PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 356, and a VL having an amino acid sequence of SEQ ID NO: 357. In another instance, an anti- PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 358, and a VL having an amino acid sequence of SEQ ID NO: 359. In -47- 49194109.1 ES Docket No.94917-0155.737601WO another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 360, and a VL having an amino acid sequence of SEQ ID NO: 361. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 362, and a VL having an amino acid sequence of SEQ ID NO: 363. In another instance, an anti-PD-1 antibody or an anti- PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 364, and a VL having an amino acid sequence of SEQ ID NO: 365. In another instance, an anti- PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 366, and a VL having an amino acid sequence of SEQ ID NO: 367. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 368, and a VL having an amino acid sequence of SEQ ID NO: 369. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 370, and a VL having an amino acid sequence of SEQ ID NO: 371. In another instance, an anti-PD-1 antibody or an anti- PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 372, and a VL having an amino acid sequence of SEQ ID NO: 373. In another instance, an anti- PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 374, and a VL having an amino acid sequence of SEQ ID NO: 375. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 376, and a VL having an amino acid sequence of SEQ ID NO: 377. In another instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 378, and a VL having an amino acid sequence of SEQ ID NO: 379. In one instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 380, a VH CDR2 having an amino acid sequence of SEQ ID NO: 381, a VH CDR3 having an amino acid sequence of SEQ ID NO: 382, VL CDR1 having an amino acid sequence of SEQ ID NO: 383, a VL CDR2 having an amino acid sequence of SEQ ID NO: 384, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 385. In one instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 386, a VH CDR2 having an amino acid sequence of SEQ ID NO: 387, a VH CDR3 having an amino acid sequence of SEQ -48- 49194109.1 ES Docket No.94917-0155.737601WO ID NO: 388, VL CDR1 having an amino acid sequence of SEQ ID NO: 389, a VL CDR2 having an amino acid sequence of SEQ ID NO: 390, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 391. In one instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 392, a VH CDR2 having an amino acid sequence of SEQ ID NO: 393, a VH CDR3 having an amino acid sequence of SEQ ID NO: 394, VL CDR1 having an amino acid sequence of SEQ ID NO: 395, a VL CDR2 having an amino acid sequence of SEQ ID NO: 396, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 397. In one instance, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 398, a VH CDR2 having an amino acid sequence of SEQ ID NO: 399, a VH CDR3 having an amino acid sequence of SEQ ID NO: 400, VL CDR1 having an amino acid sequence of SEQ ID NO: 401, a VL CDR2 having an amino acid sequence of SEQ ID NO: 402, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 403. In some embodiments, the antibody or antigen binding fragment thereof is an anti-PD-L1 antibody or antigen binding fragment. Programmed death-ligand 1 (PD-L1) is a ligand for an immunosuppressive receptor "programmed death receptor 1 (PD-1)" that is predominantly expressed in activated T and B cells, which can negatively regulate antigen receptor signaling. The ligands (PD-L1 and PD-L2) for PD-1 may be constitutively expressed or may be derived into a number of cell types, including non-hematopoietic cell tissues and various tumor types. PD-L1 is expressed in B cells, T cells, bone marrow cells and dendritic cells (DCs), but also on non- lymphatic organs such as peripheral cells, pseudo-vascular endothelial cells and heart, lungs, etc. A non-limiting, exemplary, human PD-L1 amino acid sequence is MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWE MEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMI SYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVL SGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNE RTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET (SEQ ID NO: 330) In one embodiment, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment of the disclosure comprises a combination of a heavy chain variable region (VH) and a light chain variable region (VL) described herein. In another embodiment, an anti-PD-L1 antibody or an anti- -49- 49194109.1 ES Docket No.94917-0155.737601WO PD-L1 antigen binding fragment of the disclosure comprises a combination of complementarity determining regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) described herein. In one embodiment, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment of the disclosure comprises a modified Avelumab (Bavencio, 451238, KXG2PJ551I, MSB-0010682, MSB-0010718C, PF-06834635, CAS 1537032-82-8: EMD Serono, Merck & Co., Merck KGaA, Merck Serono, National Cancer Institute (NCI), Pfizer), Durvalumab (Imfinzi, 28X28X9OKV (UNII code), MEDI-4736, CAS 1428935-60-7: AstraZeneca, Celgene, Children's Hospital Los Angeles (CHLA), City of Hope National Medical Center, MedImmune, Memorial Sloan-Kettering Cancer Center, Mirati Therapeutics, National Cancer Institute (NCI), Samsung Medical Center (SMC), Washington University), Atezolizumab (Tecentriq, 52CMI0WC3Y, MPDL-3280A, RG-7446, RO-5541267, CAS 1380723-44-3: Academisch Medisch Centrum (AMC), Chugai Pharmaceutical, EORTC, Genentech, Immune Design (Merck & Co.), Memorial Sloan-Kettering Cancer Center, National Cancer Institute (NCI), Roche, Roche Center for Medical Genomics), Sugemalimab (CS-1001, WBP-3155: CStone Pharmaceuticals, EQRx, Pfizer), KN- 046 (CAS 2256084-03-2: Jiangsu Alphamab Biopharmaceuticals, Sinovent), APL-502 (CBT-502, TQB-2450: Apollomics, Jiangsu Chia Tai Tianqing Pharmaceutical), Envafolimab (3D-025, ASC- 22, KN-035, hu56V1-Fc-m1, CAS 2102192-68-5: 3D Medicines, Ascletis, Jiangsu Alphamab Biopharmaceuticals, Suzhou Alphamab, Tracon Pharmaceuticals, Inc.), Bintrafusp alfa (M-7824, MSB-0011359C, NW9K8C1JN3, CAS 1918149-01-5: EMD Serono, GlaxoSmithKline, Merck KGaA, National Cancer Institute (NCI)), STI-1014 (STI-A1014, ZKAB-001: Lee's Pharmaceutical, Sorrento Therapeutics), PD-L1 t-haNK (ImmunityBio, NantKwest), A-167 (HBM-9167, KL-A167: Harbour BioMed, Sichuan Kelun-Biotech Biopharmaceutical), IMC-001 (STI-3031, STI-A-1015, STI-A1015, ImmuneOncia Therapeutics, Sorrento Therapeutics), HTI- 1088 (SHR-1316: Atridia, Jiangsu Hengrui), IO-103 (IO Biotech), CX-072 (CytomX Therapeutics), AUPM-170 (CA-170: Aurigene, Curis), GS-4224 (Gilead), ND-021 (NM21-1480, PRO-1480: CStone Pharmaceuticals, Numab Therapeutics), BNT-311 (DuoBody-PD-L1x4-1BB, GEN-1046: BioNTech, Genmab), BGB-A333 (BeiGene), IBI-322 (Innovent Biologics), NM-01 (Nanomab Technology, Shanghai First People's Hospital), LY-3434172 (Eli Lilly), LDP (Dragonboat Biopharmaceutical), CDX-527 (Celldex Therapeutics), IBI-318 (Innovent Biologics, Lilly), 89Zr-DFO-REGN3504 (Regeneron), ALPN-202 (CD80 vIgD-Fc: Alpine Immune Sciences), INCB-086550 (Incyte), LY-3415244 (Eli Lilly), SHR-1701 (Jiangsu Hengrui), JS-003 -50- 49194109.1 ES Docket No.94917-0155.737601WO (JS003-30, JS003-SD: Shanghai Junshi Biosciences), HLX-20 (PL2#3: Henlix Biotech, Shanghai Henlius Biotech), ES-101 (INBRX-105, INBRX-105-1: Elpiscience BioPharma, Inhibrx), MSB- 2311 (MabSpace Biosciences), PD-1-Fc-OX40L (SL-279252, TAK-252: Heat Biologics, Shattuck Labs, Takeda), FS-118, FS118 mAb2, LAG-3 / PD-L1 mAb2: F-star Therapeutics, Merck & Co., Merck KGaA), FAZ-053 (LAE-005: Laekna Therapeutics, Novartis), Lodapolimab (LY-3300054, NR4MAD6PPB, CAS 2118349-31-6: Eli Lilly), MCLA-145 (Incyte, Merus), BMS-189 (BMS- 986189, PD-L1-Milla from Bristol-Myers Squibb), Cosibelimab (CK-301, TG-1501, CAS 2216751-26-5: Checkpoint Therapeutics, Dana-Farber Cancer Institute, Samsung Biologics, TG Therapeutics), IL-15Ralpha-SD / IL-15 (KD-033: Kadmon), WP-1066 (CAS 857064-38-1: M.D. Anderson Cancer Center, Moleculin Biotech), BMS-936559 (MDX-1105: Bristol-Myers Squibb, Medarex, National Institute Allergy Infect Dis.), BMS-986192 (Bristol-Myers Squibb), RC-98 (RemeGen), CD-200AR-L (CD200AR-L: OX2 Therapeutics, University of Minnesota), ATA- 3271 (Atara Biotherapeutics), IBC-Ab002 (ImmunoBrain Checkpoint), BMX-101 (Biomunex Pharmaceuticals), AVA-04-VbP (Avacta), ACE-1708 (Acepodia Biotech), KY-1043 (Kymab, Provenance Biopharmaceuticals), ACE-05 (YBL-013: Y-Biologics), ONC-0055 (ONC0055, PRS-344 S-095012: Pieris Pharmaceuticals, Servier), TLJ-1-CK (I-Mab Biopharma), GR-1405 (Chinese Academy of Medical Sciences), PD-1ACR-T (Taipei Medical University), N-809 (N- IL15 / PD-L1: ImmunityBio), CB-201 (Crescendo Biologics), MEDI-1109 (MedImmune), AVA- 004 (AVA-04: Avacta), CA-327 (Aurigene, Curis), ALN-PDL (Alnylam Pharmaceuticals), KY- 1003 (Kymab), CD22(aPD-L1)CAR-T cells (SL-22P: Hebei Senlang Biotechnology), ATA-2271 (M28z1XXPD-1DNR CAR T cells: Atara Biotherapeutics), and Zeushield cytotoxic T lymphocytes (Second Xiangya Hosp Central South Univ.). In some embodiments, the anti-PD-L1 antibody is Avelumab, Durvalumab, Atezolizumab, Sugemalimab, Envafolimab, Lodapolimab, or Cosibelimab, or a modified version thereof. In some embodiments, the anti-PD-L1 antibody is Avelumab, Durvalumab, Atezolizumab, Sugemalimab, Envafolimab, Lodapolimab, or Cosibelimab. In some embodiments, the antibody is a biosimilar of Avelumab, Durvalumab, Atezolizumab, Sugemalimab, Envafolimab, Lodapolimab, or Cosibelimab. TABLE 1 provides the sequences of exemplary anti-PD-L1 antibodies and anti-PD-L1 antigen binding fragments that can be modified to prepare anti-PD-L1 immunoconjugates. TABLE 1 also provides exemplary combinations of CDRs that can be utilized in a modified anti-PD-L1 -51- 49194109.1 ES Docket No.94917-0155.737601WO immunoconjugate. Reference to an anti-PD-L1 antibody herein may alternatively refer to an anti- PD-L1 antigen binding fragment. In some embodiments, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of any one of SEQ ID NOS: 232, 234, 236, 238, 242, 244, or 248. An anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of any one of SEQ ID NOS: 233, 235, 237, 239, 243, 245, or 249. In one instance, an anti-PD-L1 antibody or an anti- PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of SEQ ID NO: 232, and a light chain or VL having an amino acid sequence of SEQ ID NO: 233. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of SEQ ID NO: 234, and a light chain or VL having an amino acid sequence of SEQ ID NO: 235. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of SEQ ID NO: 236, and a light chain or VL having an amino acid sequence of SEQ ID NO: 237. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of SEQ ID NO: 238, and a light chain or VL having an amino acid sequence of SEQ ID NO: 239. In another instance, an anti-PD- L1 antibody or an anti-PD-L1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 242, and a VL having an amino acid sequence of SEQ ID NO: 243. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a VH having an amino acid sequence of SEQ ID NO: 244, and a VL having an amino acid sequence of SEQ ID NO: 245. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of SEQ ID NO: 248, and a light chain or VL having an amino acid sequence of SEQ ID NO: 249. In some embodiments, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence of any one of SEQ ID NOS: 232, 234, 236, 238, 242, 244, or 248, or a portion corresponding to a VH thereof. An anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a light chain or VL having an amino acid sequence of any one of SEQ ID NOS: 233, 235, 237, 239, 243, 245, or 249, or a portion corresponding to a VL thereof. In one instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence shown in SEQ -52- 49194109.1 ES Docket No.94917-0155.737601WO ID NO: 232, and a light chain or VL having an amino acid sequence shown in SEQ ID NO: 233. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence shown in SEQ ID NO: 234, and a light chain or VL having an amino acid sequence shown in SEQ ID NO: 235. In another instance, an anti-PD- L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence shown in SEQ ID NO: 236, and a light chain or VL having an amino acid sequence shown in SEQ ID NO: 237. In another instance, an anti-PD-L1 antibody or an anti-PD- L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence shown in SEQ ID NO: 238, and a light chain or VL having an amino acid sequence shown in SEQ ID NO: 239. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 242, and a VL having an amino acid sequence shown in SEQ ID NO: 243. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a VH having an amino acid sequence shown in SEQ ID NO: 244, and a VL having an amino acid sequence shown in SEQ ID NO: 245. In another instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a heavy chain or VH having an amino acid sequence shown in SEQ ID NO: 248, and a light chain or VL having an amino acid sequence shown in SEQ ID NO: 249. In one instance, an anti-PD-L1 antibody or an anti-PD-L1 antigen binding fragment comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 250, a VH CDR2 having an amino acid sequence of SEQ ID NO: 251, a VH CDR3 having an amino acid sequence of SEQ ID NO: 252, VL CDR1 having an amino acid sequence of SEQ ID NO: 253, a VL CDR2 having an amino acid sequence of SEQ ID NO: 254, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 255. In one instance, an anti-PD-L1 antibody comprises a single domain binding antibody having an amino acid sequence of SEQ ID NO: 256, a tri-specific fusion single chain antibody construct having an amino acid sequence of SEQ ID NO: 257, or a bispecific tetrameric antibody like engager having an amino acid sequence of SEQ ID NO: 258. -53- 49194109.1 ES Docket No.94917-0155.737601WO TABLE 1 – Exemplary Antibodies for Immune Cell Associated Antigens Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Tislelizuma PD-1 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGK 332 b, Baizean, GLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVSLKLSSVT 0KVO411B AADTAVYYCARAYGNYWYIDVWGQGTTVTVSSASTKGPSVFP 3N, BGB- LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA A317, VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES hu317- KYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVAV 1 / IgG4mt2 SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVV Heavy HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS Chain (VH QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL in Bold) DSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS LSLGK Tislelizuma PD-1 DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQP 333 b, Baizean, PKLLINYAFHRFTGVPDRFSGSGYGTDFTLTISSLQAEDVAVY 0KVO411B YCHQAYSSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS 3N, BGB- VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS A317, LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC hu317- 1 / IgG4mt2 Light Chain (VL in Bold) Sintilimab, PD-1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPG 334 Tyvyt, IBI- QGLEWMGLIIPMFDTAGYAQKFQGRVAITVDESTSTAYMELS 308 Heavy SLRSEDTAVYYCARAEHSSTGTFDYWGQGTLVTVSSASTKGPS Chain (VH VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT in Bold) FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP -54- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGK Sintilimab, PD-1 DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGK 335 Tyvyt, IBI- APKLLISAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 308 Light CQQANHLPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS Chain (VL VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS in Bold) LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Toripalimab, PD-1 QGQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQA 336 TeRuiPuLi, PIHGLEWIGVIESETGGTAYNQKFKGRVTITADKSTSTAYMEL Terepril, SSLRSEDTAVYYCAREGITTVATTYYWYFDVWGQGTTVTVSS Tuoyi, JS- ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA 001, TAB- LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS 001 Heavy NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT Chain (VH PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST in Bold) YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK Toripalimab, PD-1 DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQ 337 TeRuiPuLi, KPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAED Terepril, VGVYYCFQGSHVPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLK Tuoyi, JS- SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 001, TAB- DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 001 Light Chain (VL in Bold) Camrelizum PD-1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAP 338 ab, HR- GKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQM 301210, NSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVF INCSHR- PLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 01210, AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE SHR-1210 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD -55- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Heavy VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV Chain (VH LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP in Bold) SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL SLSLGK Camrelizum PD-1 DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGK 339 ab, HR- APKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATY 301210, YCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA INCSHR- SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 01210, LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SHR-1210 Light Chain (Light Chain in Bold) Cemiplimab, PD-1 EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPG 340 Cemiplimab KGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMN -rwlc, SLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSASTKGPSVF LIBTAYO® PLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP , AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 6QVL057IN SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD T, VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV H4H7798N, LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP REGN- SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 2810, SAR- LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL 439684 SLSLGK Heavy Chain (VH in Bold) Cemiplimab, PD-1 DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAP 341 Cemiplimab NLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYC -rwlc, QQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPPSDEQLKSGTASVV -56- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment LIBTAYO® CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS , TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 6QVL057IN T, H4H7798N, REGN- 2810, SAR- 439684 Light Chain (VL in Bold) Lambrolizu PD-1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAP 346 mab, GQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYME Pembrolizu LKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSAST mab, KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS KEYTRUD GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK A®, MK- VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV 3475, SCH- TCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV 900475, VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ h409A11 VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY Heavy KTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH Chain (VH YTQKSLSLSLGK in Bold) Lambrolizu PD-1 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQK 347 mab, PGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDF Pembrolizu AVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS mab, GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD KEYTRUD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC A®, MK- 3475, SCH- 900475, h409A11 -57- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Light Chain (VL in Bold) Lambrolizu PD-1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPG 348 mab, QGLEWMGGFPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQ Pembrolizu FDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VH Lambrolizu PD-1 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPG 349 mab, QAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYC Pembrolizu QHSRDLPLTFGGGTKVEIK mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VL Nivolumab, PD-1 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGK 350 Nivolumab GLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLR BMS, AEDTAVYYCATNDDYWGQGTLVTVSS OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VH -58- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Nivolumab, PD-1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 351 Nivolumab LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSS BMS, NWPRTFGQGTKVEIK OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VL Prolgolimab, PD-1 QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQVP 352 Forteca, GKGLEWVSAIDTGGGRTYYADSVKGRFAISRVNAKNTMYLQ BCD-100 MNSLRAEDTAVYYCARDEGGGTGWGVLKDWPYGLDAWGQ Heavy GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV Chain (VH TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC in Bold) NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK Prolgolimab, PD-1 QPVLTQPLSVSVALGQTARITCGGNNIGSKNVHWYQQKPGQ 353 Forteca, APVLVIYRDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADY BCD-100 YCQVWDSSTAVFGTGTKLTVLQRTVAAPSVFIFPPSDEQLKSGT Light Chain ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST (VL in YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Bold) Balstilimab, PD-1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAP 354 1Q2QT5M7 GKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQ EO, AGEN- MNSLRAEDTAVYYCASNGDHWGQGTLVTVSSASTKGPSVFPL 2034, APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV AGEN- LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK 2034w YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS -59- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Heavy QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH Chain (VH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ in Bold) EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLG Balstilimab, PD-1 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQ 355 1Q2QT5M7 APRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYY EO, AGEN- CQQYNNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS 2034, VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS AGEN- LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 2034w Light Chain (VL in Bold) Dostarlimab, PD-1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPG 356 ANB-011, KGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMN GSK- SLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTKGPSVFP 4057190A, LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA P0GVQ9A4 VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES S5, TSR- KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 042, WBP- SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL 285 Heavy HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS Chain (VH QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL in Bold) DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS LSLGK Dostarlimab, PD-1 DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGK 357 ANB-011, APKLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATY GSK- YCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA 4057190A, SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS P0GVQ9A4 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC S5, TSR- 042, WBP- -60- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment 285 Light Chain (VL in Bold) Serplulimab, PD-1 358 HLX-10 QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYGMSWIRQAPG Heavy KGLEWSTISGGGSNIYYADSVKGRFTISRDNAKNSLYLQMNSL Chain (VH RAEDTAVYYCVSYYYGIDFWGQGTSVTVSSASKYGPSVFPLAPC in Bold) SRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGP PCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSL GK Serplulimab, PD-1 359 HLX-10 DIQMTQSPSSLSASVGDRVTITCKASQDVTTAVAWYQQKPGK Light Chain APKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATY (VL in YCQQHYTIPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA Bold) SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Retifanlima PD-1 QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAP 360 b, GQGLEWIGVIHPSDSETWLDQKFKDRVTITVDKSTSTAYMEL 2Y3T5IF01 SSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSSASTKGPS Z, VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT INCMGA- FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR 00012, VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV INCMGA- VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL 0012, MGA- TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT 012 Heavy LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP Chain (VH PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK in Bold) SLSLSLG -61- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Retifanlima PD-1 EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQ 361 b, KPGQPPKLLIHAASNQGSGVPSRFSGSGSGTDFTLTISSLEPED 2Y3T5IF01 FAVYFCQQSKEVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLK Z, SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK INCMGA- DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 00012, INCMGA- 0012, MGA- 012 Light Chain (VL in Bold) Sasanlimab, PD-1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAP 362 LZZ0IC2E GQGLEWMGNIYPGSSLTNYNEKFKNRVTMTRDTSTSTVYME WP, PF- LSSLRSEDTAVYYCARLSTGTFAYWGQGTLVTVSSASTKGPSV 06801591, FPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF RN-888 PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV Heavy ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV Chain (VH DVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT in Bold) VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGK Sasanlimab, PD-1 DIVMTQSPDSLAVSLGERATINCKSSQSLWDSGNQKNFLTWY 363 LZZ0IC2E QQKPGQPPKLLIYWTSYRESGVPDRFSGSGSGTDFTLTISSLQ WP, PF- AEDVAVYYCQNDYFYPHTFGGGTKVEIKRTVAAPSVFIFPPSDE 06801591, QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ RN-888 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR Light GEC Chain (VL in Bold) Spartalizum PD-1 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAT 364 ab, NVP- GQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYME -62- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment LZV-184, LSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPS PDR-001, VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT QOG25L6Z FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR 8Z Heavy VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV Chain (VH VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL in Bold) TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLG Spartalizum PD-1 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQ 365 ab, NVP- QKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAE LZV-184, DAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQL PDR-001, KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS QOG25L6Z KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE 8Z Light C Chain (VL in Bold) Cetrelimab, PD-1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPG 366 JNJ-3283, QGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSS JNJ- LRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLVTVSSASTK 63723283, GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG LYK98WP9 VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKV 1F Heavy DKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT Chain (VH CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV in Bold) SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQV YTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLGK Cetrelimab, PD-1 EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQA 367 JNJ-3283, PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC JNJ- QQRNYWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV 63723283, -63- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment LYK98WP9 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS 1F Light STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Chain (VL in Bold) Tebotelimab PD-1 368 , MGD-013 DIQMTQSPSSLSASVGDRVTITCRASQDVSSVVAWYQQKPGK Heavy APKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATY Chain (VL YCQQHYSTPWTFGGGTKLEIKGGGSGGGGQVQLVQSGAEVKK in Bold) PGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSE TWLDQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHY GTSPFAYWGQGTLVTVSSGGCGGGEVAACEKEVAALEKEVAAL EKEVAALEKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLYITR EPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEA LHNHYTQKSLSLSLG Tebotelimab PD-1 369 , MGD-013 EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQ Light Chain KPGQPPKLLIHAASNQGSGVPSRFSGSGSGTDFTLTISSLEPED (VL in FAVYFCQQSKEVPYTFGGGTKVEIKGGGSGGGGQVQLVQSGA Bold) EVKKPGASVKVSCKASGYTFTDYNMDWVRQAPGQGLEWMGDI NPDNGVTIYNQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYY CAREADYFYFDYWGQGTTLTVSSGGCGGGKVAACKEKVAALKE KVAALKEKVAALKE Pidilizumab, PD-1 QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAP 370 CT-011, GQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQI MDV-9300 TSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSV Heavy FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF Chain (VH PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV in Bold) EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS -64- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK Pidilizumab, PD-1 EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAP 371 CT-011, KLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYC MDV-9300 QQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVV Light Chain CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS (VL in TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Bold) SG-001 VH PD-1 QVQLVESGGGVVQPGRSLRLTCKASGLTFSSSGMHWVRQAPGK 372 GLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLR AEDTAVYYCATNNDYWGQGTLVTVSS SG-001 VL PD-1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 373 LLIYTASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQYS NWPRTFGQGTKVEIK mpLZM- PD-1 EVQLQQSGPVLVKPGASVKMSCKASGYTFTSYYMYWVKQSHGK 374 009 VH SLEWIGGVNPSNGGTNFNEKFKSKATLTVDKSSSTAYMELNSLTS (Murine EDSAVYYCARRDYRYDMGFDYWGQGTTLTVSS Precursor of LZM-009) mpLZM- PD-1 QIVLTQSPAIMSASPGEKVTMTCRASKGVSTSGYSYLHWYQQKP 375 009 VL GSSPRLLIYLASYLESGVPVRFSGSGSGTSYSLTISRMEAEDAATY (Murine YCQHSRELPLTFGTGTRLEIK Precursor of LZM-009) LZM-009 PD-1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMYWVRQAPG 376 VH QGLEWMGGVNPSNGGTNFNEKFKSRVTITADKSTSTAYMELSSL RSEDTAVYYCARRDYRYDMGFDYWGQGTTVTVSS LZM-009 PD-1 EIVLTQSPATLSLSPGERATISCRASKGVSTSGYSYLHWYQQKPG 377 VL QAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFATYYC QHSRELPLTFGTGTKVEIK -65- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Budigalimab PD-1 EIQLVQSGAEVKKPGSSVKVSCKASGYTFTHYGMNWVRQAP 378 , GQGLEWVGWVNTYTGEPTYADDFKGRLTFTLDTSTSTAYME 6VDO4TY3 LSSLRSEDTAVYYCTREGEGLGFGDWGQGTTVTVSSASTKGP OO, ABBV- SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH 181, PR- TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK 1648817 KVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV Heavy TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV Chain (VH VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP in Bold) QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK Budigalimab PD-1 DVVMTQSPLSLPVTPGEPASISCRSSQSIVHSHGDTYLEWYLQ 379 , KPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAED 6VDO4TY3 VGVYYCFQGSHIPVTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS OO, ABBV- GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD 181, PR- STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 1648817 Light Chain (VL in Bold) Lambrolizu PD-1 NYYMY 380 mab, Pembrolizu mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VH CDR1 Lambrolizu PD-1 GINPSNGGTNFNEKFKN 381 mab, -66- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment Pembrolizu mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VH CDR2 Lambrolizu PD-1 RDYRFDMGFDY 382 mab, Pembrolizu mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VH CDR3 Lambrolizu PD-1 RASKGVSTSGYSYLH 383 mab, Pembrolizu mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VL CDR1 Lambrolizu PD-1 LASYLES 384 mab, Pembrolizu mab, -67- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VL CDR2 Lambrolizu PD-1 QHSRDLPLT 385 mab, Pembrolizu mab, KEYTRUD A®, MK- 3475, SCH- 900475, h409A11 VL CDR3 Nivolumab, PD-1 NSGMH 386 Nivolumab BMS, OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VH CDR1 Nivolumab, PD-1 VIWYDGSKRYYADSVKG 387 Nivolumab BMS, OPDIVO®, BMS- 936558, MDX-1106, -68- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment ONO-4538 VH CDR2 Nivolumab, PD-1 NDDY 388 Nivolumab BMS, OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VH CDR3 Nivolumab, PD-1 RASQSVSSYLA 389 Nivolumab BMS, OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VL CDR1 Nivolumab, PD-1 DASNRAT 390 Nivolumab BMS, OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VL CDR2 Nivolumab, PD-1 QQSSNWPRT 391 Nivolumab BMS, -69- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment OPDIVO®, BMS- 936558, MDX-1106, ONO-4538 VL CDR3 Serplulimab, PD-1 FTFSNYGMS 392 HLX-10 VH CDR1 Serplulimab, PD-1 TISGGGSNIY 393 HLX-10 VH CDR2 Serplulimab, PD-1 VSYYYGIDF 394 HLX-10 VH CDR3 Serplulimab, PD-1 KASQDVTTAVA 395 HLX-10 VL CDR1 Serplulimab, PD-1 WASTRHT 396 HLX-10 VL CDR2 Serplulimab, PD-1 QQHYTIPWT 397 HLX-10 VL CDR3 SG-001 VH PD-1 GLTFSSSG 398 CDR1 SG-001 VH PD-1 IWYDGSKR 399 CDR2 SG-001 VH PD-1 ATNNDY 400 CDR3 SG-001 VL PD-1 RASQSVSSYLA 401 CDR1 -70- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment SG-001 VL PD-1 TASNRAT 402 CDR2 SG-001 VL PD-1 QQYSNWPRT 403 CDR3 Avelumab PD-L1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPG 232 (Generic) KGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNS Bavencio LRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPS (Brand) VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 451238 FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK KXG2PJ551 VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT I CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV MSB- SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 0010682 VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK MSB- TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY 0010718C TQKSLSLSPGK PF- 06834635 Heavy Chain (VH in Bold) Avelumab PD-L1 QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPG 233 (Generic) KAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEA Bavencio DYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQA (Brand) NKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNK 451238 YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS KXG2PJ551 I MSB- 0010682 MSB- 0010718C PF- -71- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment 06834635 Light Chain (VL in Bold) Durvalumab PD-L1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAP 234 (Generic) GKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQ Imfinzi MNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSAS (Brand) TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT 28X28X9O SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK KV (UNII VDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRT code) PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST MEDI-4736 YRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP Heavy REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE Chain (VH NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL in Bold) HNHYTQKSLSLSPGK Durvalumab PD-L1 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQ 235 (Generic) APRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY Imfinzi CQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS (Brand) VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 28X28X9O LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC KV (UNII code) MEDI-4736 Light Chain (VL in Bold) Atezolizuma PD-L1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPG 236 b (Generic) KGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMN Tecentriq SLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPS (Brand) VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 52CMI0WC FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK 3Y VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT -72- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment MPDL- CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVV 3280A SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ RG-7446 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY RO- KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH 5541267 YTQKSLSLSPGK Heavy Chain (VH in Bold) Atezolizuma PD-L1 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGK 237 b (Generic) APKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY Tecentriq CQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS (Brand) VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 52CMI0WC LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 3Y MPDL- 3280A RG-7446 RO- 5541267 Light Chain (VL in Bold) Sugemalima PD-L1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPG 238 b (Generic) KGLEWVSGISGSGGFTYYADSVKGRFTISRDNSKNTLYLQMN CS-1001 SLRAEDTAVYYCAKPPRGYNYGPFDYWGQGTLVTVSSASTKG WBP-3155 PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV Heavy HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVD Chain (VH KRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTC in Bold) VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQV YTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK -73- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLGK Sugemalima PD-L1 SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQA 239 b (Generic) PVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYY CS-1001 CQVWDSSSDHVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQA WBP-3155 NKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK Light YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Chain (VL in Bold) JS-003 PD-L1 QGQLQESGPSLVKPSQTLSLTCTVSGDSITRGYWNWIRKHPGKGL 242 JS003-30 EYIGYISYTGSTYSNLSLKSRVTISRDTSKNQYYLKLSSVTAADTA JS003-SD VYYCATSTGWLDPVDYWGQGTLVTVSS VH JS-003 PD-L1 DIVMTQSPDSLAVSLGERATINCKASQNVDTSVAWFQQKPGQPP 243 JS003-30 KALIYSASFRYSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQ JS003-SD YYGYPFTFGQGTKLEIK VL HLX-20 PD-L1 EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYTMNWVRQAPGK 244 PL2#3 VH GLEWVSSISSGSDYLYYADSVKGRFTISRDNAKNSLYLQMNSLRA EDTAVYYCARNELRWYPQAGAFDRWGQGTMVTVSS HLX-20 PD-L1 QSVVTQPPSMSAAPGQRVTISCSGSSSYIESSYVGWYQQLPGTAP 245 PL2#3 VL RLLIYDDDMRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCEI WRSGLGGVFGGGTKLTVL Lodapolima PD-L1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPG 248 b (Generic) QGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSS LY-3300054 LRSEDTAVYYCARSPDYSPYYYYGMDVWGQGTTVTVSSASTK NR4MAD6 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG PPB Heavy VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV Chain (VH DKRVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTP in Bold) EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN -74- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK Lodapolima PD-L1 QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGT 249 b (Generic) APKLLIYGNSNRPSGVPDRFSGSKSGTSASLAISGLQSEDEADY LY-3300054 YCQSYDSSLSGSVFGGGIKLTVLGQPKAAPSVTLFPPSSEELQAN NR4MAD6 KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKY PPB Light AASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPAECS Chain (VL in Bold) HLX-20 PD-L1 SYTMN 250 PL2#3 VH CDR1 HLX-20 PD-L1 SISSGSDYLYYADSVKG 251 PL2#3 VH CDR2 HLX-20 PD-L1 NELRWYPQAGAFDR 252 PL2#3 VH CDR3 HLX-20 PD-L1 SGSSSYIESSYVG 253 PL2#3 VL CDR1 HLX-20 PD-L1 DDDMRPS 254 PL2#3 VL CDR2 HLX-20 PD-L1 EIWRSGLGGV 255 PL2#3 VL CDR3 Envafolimab PD-L1 QVQLVESGGGLVQPGGSLRLSCAASGKMSSRRCMAWFRQAP 256 (Generic) GKERERVAKLLTTSGSTYLADSVKGRFTISRDNSKNTVYLQM 3D-025 NSLRAEDTAVYYCAADSFEDPTCTLVTSSGAFQYWGQGTLVT ASC-22 VSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV KN-035 TCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV -75- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment hu56V1-Fc- VSVLTVLHQDWLNGKEYKCKVSNKALPAGIEKTISKAKGQPREP m1 single- QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY domain KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH antibody YTQKSLSLSPGK (VH in Bold) ND-021 PD-L1 DIQMTQSPASLSASVGDRVTITCQASQSIGTYLAWYQQKPGKPPK 257 NM21-1480 LLIYRAFILASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQSNF PRO-1480 YSDSTTIGPNAFGTGTKVTVLGGGGGSEVQLVESGGGLVQPGGS Tri-specific LRLSCAASGFSFSANYYPCWVRQAPGKGLEWIGCIYGGSSDITYD fusion ANWTKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARSAWYS single-chain GWGGDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSIQMTQ antibody SPSSLSASVGDRVTITCQASQSISNRLAWYQQKPGKAPKLLIYSAS construct TLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQSTYYGNDGN AFGTGTKVTVLGGGGGSEVQLVESGGGLVQPGGSLRLSCAASGF SFNSDYWIYWVRQAPGKGLEWIASIYGGSSGNTQYASWAQGRFT ISRDNSKNTVYLQMNSLRAEDTAVYFCARGYVDYGGATDLWGQ GTLVTVSSGGGGSGGGGSIQMTQSPSSLSASVGDRVTITCQSSESV YSNNQLSWYQQKPGQPPKLLIYDASDLASGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCAGGFSSSSDTAFGGGTKLTVLGGGGGSGG GGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSLSS NAMGWVRQAPGKGLEYIGIISVGGFTYYASWAKGRFTISRDNSK NTVYLQMNSLRAEDTATYFCARDRHGGDSSGAFYLWGQGTLVT VSS ACE-05 PD-L1 QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQG 258 YBL-013 LEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSED Bispecific TAVYYCAKPRDGYNLVAFDIWGQGTMVTVSSASTKGPSVFPLAP tetrameric SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL antibody- QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS like cell CDKTHTCPPCPAPELLGGPGGGGSEVQLQQSGPELVKPGPSMKIS engager CKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQK (ALiCE) FKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDW -76- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment comprising YFDVWGQGTTLTVFSQMQLVQSGAEVKKPGSSVKVSCKASGGT two identical FSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITAD light chains KSTSTAYMELSSLRSEDTAVYYCAKPRDGYNLVAFDIWGQGTM (LC) VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS consisting of WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV antigen NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPGGGGSDIQ binding MTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLI domains YYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTL (ABDs) PWTFAGGTKLEIKRQLVLTQPPSVSGAPGQRVTISCTGSSSNIGAG targeting YDVHWYQQLPGAAPKLLIYGDINRPSGVPDRFSGSKSGISASLAIT programmed GLQAEDEADYYCQSYDSSLSGGVFGGGTKLTVLRTVAAPSVFIFP cell death- PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV ligand 1 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS (PD-L1), FNRGEC and two different heavy chain (HC)-like chains (ACE-05- VH and ACE-05- VL) each consisting of an anti-PD- L1 ABD and an anti-CD3 ABD ; wherein each HC comprises a G4S linker -77- 49194109.1 ES Docket No.94917-0155.737601WO Antibody Antigen Sequence SEQ or Ag- Bound ID binding NO fragment (SEQ ID NO: 691) between the hinge region and the second ABD Modification to Fc region Disclosed herein are antibodies or antigen binding fragments thereof that comprise an Fc region, wherein the Fc region comprises at least one covalently linked linker. In some embodiments, the linker is a chemical linker. In some embodiments, the chemical linker is covalently attached to a tyrosine, aspartic acid, glutamic acid, arginine, histidine, or lysine residue. In some embodiments, the chemical linker is covalently attached to a lysine, cysteine, or tyrosine residue. In some embodiments, the chemical linker is covalently attached to a cysteine residue. In some embodiments, the chemical linker is covalently attached to a lysine residue. In some embodiments, the chemical linker is covalently attached to a constant region of the antibody. In some embodiments, the antibody comprises an Fc region. In some embodiments, the Fc region is an IgG Fc region, an IgA Fc region, an IgD Fc region, an IgM Fc region, or an IgE Fc region. In some embodiments, the Fc region is an IgG Fc region, an IgA Fc region, or an IgD Fc region. In some embodiments, the Fc region is a human Fc region. In some embodiments, the Fc region is a humanized. Fc region. In some embodiments, the Fc region is an IgG Fc region. In some instances, an IgG Fc region is an IgG1 Fc region, an IgG2a Fc region, or an IgG4 Fc region. One or more mutations may be introduced in an Fc region to reduce Fc-mediated effector functions of an antibody or antigen-binding fragment such as, for example, antibody-dependent cellular cytotoxicity (ADCC) and / or complement function. In some instances, a modified Fc comprises a humanized IgG4 kappa isotype that contains a S229P Fc mutation. In some instances, a modified Fc comprises a human IgG1 kappa where the heavy chain CH2 domain is engineered -78- 49194109.1 ES Docket No.94917-0155.737601WO with a triple mutation such as, for example: (a) L238P, L239E, and P335S; or (2) K248; K288; and K317. In some embodiments, the Fc region has an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at to or 18 is ES Docket No.94917-0155.737601WO attached to the Fc region at an amino acid residue at one of positions 10-30, 50-70, or 80-100 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at an amino acid residue at any one of positions 20-40, 65-85, or 90-110 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at an amino acid residue at one of positions 15-26, 55-65, or 85-90 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at an amino acid residue at any one of positions 25-35, 70-80, or 95- 105 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at an amino acid residue at any one of positions 30, 32, 72, 74, or 101 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at an amino acid residue at any one of positions K30, K32, K72, K74, or K101 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at amino acid residue 30 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at amino acid residue 32 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at amino acid residue 72 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at amino acid residue 74 of SEQ ID NO: 260. In some embodiments, the chemical linker is attached to the Fc region at amino acid residue 101 of SEQ ID NO: 260. The chemical linker can be covalently attached to one amino acid residue of an Fc region of the antibody. In some embodiments, the chemical linker is covalently attached to a non-terminal residue of the Fc region. In some embodiments, the non-terminal residue is in the CH1, CH2, or CH3 region of the antibody. In some embodiments, the non-terminal residue is in the CH2 region of the antibody. In some embodiments, the chemical linker is covalently attached at an amino acid residue of the antibody or antigen binding fragment which selectively binds a immune associated antigen (e.g., an anti-PD-1 antibody) such that the function of the antibody or antigen binding fragment is maintained (e.g., without denaturing the polypeptide). For example, when the antibody or antigen binding fragment is a human IgG (e.g., human IgG1), exposed lysine residues and exposed tyrosine residues are present at the following positions (refer to web site www.imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html by EU numbering). Exemplary exposed Lysine Residues: CH2 domain (position 246, position 248, position 274, position 288, position 290, position 317, position 320, position 322, and position 338) CH3 domain -80- 49194109.1 ES Docket No.94917-0155.737601WO (position 360, position 414, and position 439). Exemplary exposed Tyrosine Residues: CH2 domain (position 278, position 296, and position 300) CH3 domain (position 436). The human IgG, such as human IgG1, may also be modified with a lysine or tyrosine residue at any one of the positions listed above in order provide a residue which is ideally surface exposed for subsequent modification. In some embodiments, the chemical linker is covalently attached at an amino acid residue in the constant region of an antibody. In some embodiments, the chemical linker is covalently attached at an amino acid residue in the CH1, CH2, or CH3 region. In some embodiments, the chemical inker is covalently attached at an amino acid residue in the CH2 region. In some embodiments, the chemical linker may be covalently attached to one amino acid residue in the following groups of residues following EU numbering in human IgG Fc: amino acid residues 1- 478, amino acid residues 2-478, amino acid residues 1-477, amino acid residues 2-477, amino acid residues 10-467, amino acid residues 30-447, amino acid residues 50-427, amino acid residues 100-377, amino acid residues 150-327, amino acid residues 200-327, amino acid residues 240- 327, and amino acid residues 240-320. a is at on an a ES Docket No.94917-0155.737601WO six, seven, eight, nine, or ten amino acid residues of an Fc region of the antibody. The chemical linker can be covalently attached to one of two lysine residues of an Fc region of the antibody. In some embodiments, the antibody will comprise two linkers covalently attached to the Fc region of the antibody. In some embodiments, each of the two linkers will be covalently attached to a different heavy chain of the antibody. In some embodiments, each of the two linkers will be covalently attached to a different heavy chain of the antibody at a residue position which is the same. In some embodiments, each of the two linkers will be covalently attached to a different heavy chain of antibody at a residue position which is different. When the two linkers are covalently attached to residue positions which differ, any combination of the residue positions provided herein may be used in combination. Method of Modifying an Fc Region Also provided herein are method of preparing a modified Fc region of an antibody or antigen binding fragment, such as for the attachment of a linker, a conjugation handle, the IL-18 polypeptide, or any combination thereof to the antibody or antigen binding fragment. A variety of methods for site-specific modification of Fc regions of antibodies are known in the art. Modification with an affinity peptide configured to site-specifically attach linker to the antibody In some embodiments, an Fc region is modified to incorporate a linker, a conjugation handle, or a combination thereof. In some embodiments, the modification is performed by contacting the Fc region with an affinity peptide bearing a payload configured to attach a linker or other group to the Fc region, such as at a specific residue of the Fc region. In some embodiments, the linker is attached using a reactive group which forms a bond with a residue of the Fc region. In some embodiments, the affinity peptide comprises a cleavable linker. The cleavable linker is configured on the affinity peptide such that after the linker or other group is attached to the Fc region, the affinity peptide can be removed, leaving behind only the desired linker or other group attached to the Fc region. The linker or other group can then be used further to add attach additional groups, such as a cytokine or a linker attached to a cytokine, to the Fc region. Non-limiting examples of such affinity peptides can be found at least in PCT Publication No. WO2018199337A1, PCT Publication No. WO2019240288A1, PCT Publication No. WO2019240287A1, and PCT Publication No. WO2020090979A1, each of which is incorporated by reference as if set forth herein in its entirety. In some embodiments, the affinity peptide is a peptide which has been modified to deliver the linker / conjugation handle payload one or more -82- 49194109.1 ES Docket No.94917-0155.737601WO specific residues of the Fc region of the antibody. In some embodiments, the affinity peptide has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identify to a peptide selected from (1) QETNPTENLYFQQKNMQCQRRFYEALHDPNLNEEQRNARIRSIRDDDC (SEQ ID NO: 261); (2) QTADNQKNMQCQRRFYEALHDPNLNEEQRNARIRSIRDDCSQSANLLAEAQQLNDAQA PQA (SEQ ID NO: 262); (3) QETKNMQCQRRFYEALHDPNLNEEQRNARIRSIRDDDC (SEQ ID NO:263); (4) QETFNKQCQRRFYEALHDPNLNEEQRNARIRSIRDDDC (SEQ ID NO: 264); (5) QETFNMQCQRRFYEALHDPNLNKEQRNARIRSIRDDDC (SEQ ID NO: 265); (6) QETFNMQCQRRFYEALHDPNLNEEQRNARIRSIKDDC (SEQ ID NO: 266); (7) QETMQCQRRFYEALHDPNLNEEQRNARIRSIKDDC (SEQ ID NO: 267); (8) QETQCQRRFYEALHDPNLNEEQRNARIRSIKDDC (SEQ ID NO: 268); (9) QETCQRRFYEALHDPNLNEEQRNARIRSIKDDC (SEQ ID NO: 269); (10) QETRGNCAYHKGQLVWCTYH (SEQ ID NO: 270); and (11) QETRGNCAYHKGQIIWCTYH (SEQ ID NO: 271), or a corresponding peptide which has been truncated at the N-terminus by one, two, three, four, or five residues. An exemplary affinity peptide with cleavable linker and conjugation handle payload capable of attaching the payload to residue K248 of an antibody as provided herein is shown below (as reported in Matsuda et al., “Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody-Drug Conjugates,” Mol. Pharmaceutics 2021, 18, 11, 4058-4066. (SEQ ID NO: Alternative affinity peptides targeting alternative residues of the Fc region are described in the references cited above for AJICAPTMtechnology, and such affinity peptides can be used to -83- 49194109.1 ES Docket No.94917-0155.737601WO attach the desired functionality to an alternative residue of the Fc region (e.g., K246, K288, etc.). For example, the disulfide group of the above affinity peptide could instead be replaced with a thioester to provide a sulfhydryl protecting group as a cleavable portion of the linking group (e.g., the relevant portion of the affinity peptide would have a structure of , or another of the cleavable linkers discussed below). Such those described in, for example “AJICAP Second Generation: Improved Chemical Site-Specific Conjugation Technology for Antibody-Drug Conjugation Technology for Antibody-Drug Conjugate Production” (Working Paper, Fujii et al., DOI: 10.26434 / chemrxiv-2023-9p5p7, chemrxiv.org / engage / chemrxiv / article- details / 63d5f7131125965a9e7df8a5 (Accessed 20 February 2023, Version 1 published 30 Jan 2023)). Exemplary affinity peptides provided therein include those shown below, wherein the left structure targets K248 of the Fc region and the right structure targets K288 of the Fc region (EU numbering). The affinity peptide of the disclosure can comprise a cleavable linker. In some embodiments, the cleavable linker of the affinity peptide connects the affinity peptide to the group which is to be attached to the Fc region and is configured such that the peptide can be cleaved after the group comprising the linker or conjugation handle has been attached. In some embodiments, the cleavable linker is a divalent group. In some embodiments, the cleavable linker can comprise a thioester group, an ester group, a sulfane group; a methanimine group; an oxyvinyl group; a thiopropanoate group; an ethane-1,2-diol group; an (imidazole-1-yl)methan-1-one group; a seleno ether group; a silylether group; a di-oxysilane group; an ether group; a di-oxymethane group; a -84- 49194109.1 ES Docket No.94917-0155.737601WO tetraoxospiro[5.5]undecane group; an acetamidoethyl phosphoramidite group; a bis(methylthio)- pyrazolopyrazole-dione group; a 2-oxo-2-phenylethyl formate group; a 4-oxybenzylcarbamate 2- N′- ES Docket No.94917-0155.737601WO , wherein: -one of A of A or B is a point of attachment to the affinity peptide; - each R2ais independently H or optionally substituted alkyl; - each R2bis independently H or optionally substituted alkyl; - R2cis a H or optionally substituted alkyl; -J is a methyl, a N, a S, a Si, or an O atom; and - r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The affinity peptide comprises a reactive group which is configured to enable the covalent attachment of the linker / conjugation handle to the Fc region. In some embodiments, the reactive group is selective for a functional group of a specific amino acid residue, such as a lysine residue, tyrosine residue, serine residue, cysteine residue, or an unnatural amino acid residue of the Fc region incorporated to facilitate the attachment of the linker. The reactive group may be any suitable functional group, such as an activated ester for reaction with a lysine (e.g., N- hydroxysuccinimide ester or a derivate thereof, a pentafluorophenyl ester, etc.) or a sulfhydryl reactive group for reaction with a cysteine (e.g., a Michael acceptor, such as an alpha-beta unsaturated carbonyl or a maleimide). In some embodiments, the reactive group is: ES Docket No.94917-0155.737601WO , wherein: - each R5a, R5b, and R5c is independently H, halogen, or optionally substituted alkyl; is of a a C, ES Docket No.94917-0155.737601WO , , in ES Docket No.94917-0155.737601WO engineering or an engineered transglutaminase; and 2) amine donor agents comprising amine donor units, linkers, and agent moieties. Non-limiting examples of such transglutaminase mediated site-specific modifications can be found at least in publications PCT Publication No. WO2020188061, US Patent Publication No. US2019194641, US Patent Publication No. US2021128743, US Patent No. US9764038, and US Patent No. US10434180, which are incorporated by reference as if set forth herein in their entirety. In another aspect, the disclosure provides an engineered Fc-containing polypeptide conjugate comprising the formula: (Fc-containing polypeptide-T-A), wherein T is an acyl donor glutamine-containing tag engineered at a specific site, wherein A is an amine donor agent, wherein the amine donor agent is site-specifically conjugated to the acyl donor glutamine-containing tag at a carboxyl terminus, an amino terminus, or at an another site in the Fc-containing polypeptide, wherein the acyl donor glutamine-containing tag comprises an amino acid sequence XXQX, wherein X is any amino acid (e.g., X can be the same or different amino acid), and wherein the engineered Fc-containing polypeptide conjugate comprises an amino acid substitution from glutamine to asparagine at position 295 (Q295N; EU numbering scheme). In some embodiments, the acyl donor glutamine-containing tag is not spatially adjacent to a reactive Lys (e.g., the ability to form a covalent bond as an amine donor in the presence of an acyl donor and a transglutaminase) in the polypeptide or the Fc-containing polypeptide. In some embodiments, the polypeptide or the Fc-containing polypeptide comprises an amino acid modification at the last amino acid position in the carboxyl terminus relative to a wild-type polypeptide at the same position. The amino acid modification can be an amino acid deletion, insertion, substitution, mutation, or any combination thereof. In some embodiments, the immunocytokine composition comprises a full length antibody heavy chain and an antibody light chain, wherein the acyl donor glutamine-containing tag is located at the carboxyl terminus of a heavy chain, a light chain, or both the heavy chain and the light chain. In some embodiments, the immunocytokine composition comprises an antibody, wherein the antibody is a monoclonal antibody, a polyclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, a minibody, a diabody, or an antibody fragment. In some embodiments, the antibody is an IgG. -89- 49194109.1 ES Docket No.94917-0155.737601WO In another aspect, provided herein is a method for preparing an engineered Fc-containing polypeptide conjugate comprising the formula: (Fc-containing polypeptide-T-A), wherein T is an the a an the the ES Docket No.94917-0155.737601WO polypeptide conjugate, the engineered Fab-containing polypeptide conjugate, or the engineered antibody conjugate) and a pharmaceutically acceptable excipient. or the an an a an a ES Docket No.94917-0155.737601WO In one embodiment, the residue at the +2 position is a non-aspartic acid, non-asparagine residue. In one embodiment, the residue at the +2 position is a non-negatively charged amino acid (an in a a a a the 20 is (c) an ES Docket No.94917-0155.737601WO immobilized antibodies, optionally recovering any unreacted compound and re-introducing such recovered compound to the solid support for reaction with immobilized antibodies, and eluting the antibody conjugates to provide an antibody composition comprising a Z moiety. In an alternative embodiment, an amino acid residue comprising a conjugation handle can be incorporated into the Fc region of the antibody (e.g., during expression of the antibody) at a desired location (e.g., any of the locations provided herein). In some embodiments, the amino acid residue comprising the conjugation handle is an unnatural amino acid. Conjugation Handle Chemistry In some embodiments, the appropriately modified Fc region of the antibody or antigen binding fragment will comprise a conjugation handle which is used to conjugate the antibody or antigen binding fragment to an IL-18 polypeptide to produce an immunocytokine composition provided herein. Any suitable reactive group capable of reacting with a complementary reactive group attached to the IL-18 polypeptide can be used as the conjugation handle. In some embodiments, the conjugation handle comprises a reagent for a Cu(I)-catalyzed or "copper-free" alkyne-azide triazole-forming reaction (e.g., strain promoted cycloadditions), the Staudinger ligation, inverse- electron-demand Diels-Alder (IEDDA) reaction, "photo-click" chemistry, tetrazine cycloadditions with trans-cyclooctenes, potassium acyl trifluoroborate (KAT) ligation or a metal-mediated process such as olefin metathesis and Suzuki- Miyaura or Sonogashira cross-coupling. In some embodiments, the conjugation handle comprises a reagent for a “copper-free” alkyne azide triazole-forming reaction. Non-limiting examples of alkynes for said alkyne, azide triazole forming reaction include cyclooctyne reagents (e.g., (1R,8S,9s)-Bicyclo[6.1.0]non-4-yn- 9-ylmethanol containing reagents, dibenzocyclooctyne-amine reagents, difluorocyclooctynes, or derivatives thereof). In some embodiments, the alkyne functional group is attached to the Fc region. In some embodiments, the azide functional group is attached to the Fc region. In some embodiments, the conjugation handle comprises a reactive group selected from azide, alkyne, tetrazine, halide, sulfhydryl, disulfide, maleimide, activated ester, alkene, aldehyde, ketone, imine, hydrazine, potassium acyl trifluoroborate, hydroxylamine (e.g., O-substituted hydroxylamine) and hydrazide. In some embodiments, the IL-18 polypeptide comprises a reactive group complementary to the conjugation handle of the Fc region. In some embodiments, the conjugation handle and the complementary conjugation handle comprise “CLICK” chemistry -93- 49194109.1 ES Docket No.94917-0155.737601WO reagents. Exemplary groups of click chemistry residue are shown in Hein et al., “Click Chemistry, A Powerful Tool for Pharmaceutical Sciences,” Pharmaceutical Research, volume 25, pages 2216– 2230 (2008); Thirumurugan et al., “Click Chemistry for Drug Development and Diverse Chemical–Biology Applications,” Chem. Rev. 2013, 113, 7, 4905–4979; US20160107999A1; US10266502B2; and US20190204330A1, each of which is incorporated by reference in its entirety. Linker Structure In some embodiments, the linker used to attach the antibody or antigen binding fragment and the IL-18 polypeptide comprises points of attachment at both moieties. The points of attachment can be any of the residues for facilitating the attachment as provided herein. The linker structure can be any suitable structure for creating the spatial attachment between the two moieties. In some embodiments, the linker provides covalent attachment of both moieties. In some embodiments, the linker is a chemical linker (e.g., not an expressed polypeptide as in a fusion protein). In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a non-peptide linker (e.g., does not consist of amino acid residues). Chemical Linkers In some embodiments, the linker is a chemical linker. In some embodiments, the chemical linker at least one which is not of amino acid residues. In some , or the or the 1- 6- ES Docket No.94917-0155.737601WO (Allyloxycarbonylamino)-1-hexanol; 4-Aminobutyraldehyde diethyl acetal; or (E)-N-(2- Aminoethyl)-4-{2-[4-(3-azidopropoxy)phenyl]diazenyl}benzamide hydrochloride. The linker can be branched or linear. In some embodiments, the linker is linear. In some embodiments, the linker is branched. In some embodiments, the linker comprises a linear portion (e.g., between the first point of attachment and the second point of attachment) of a chain of at least 10, 20, 50, 100, 500, 1000, 2000, 3000, or 5000 atoms. In some embodiments, the linker comprises a linear portion of a chain of at least 10, 20, 30, 40, or 50 atoms. In some embodiments, the linker comprises a linear portion of at least 10 atoms. In some embodiments, the linker is branched and comprises a linear portion of a chain of at least 10, 20, 50, 100, 500, 1000, 2000, 3000, or 5000 atoms. In some embodiments, the linker comprises a linear portion of at from 1 to 1000 atoms, 1 to 900 atoms, 1 to 800 atoms, 1 to 500 atoms, 1 to 400 atoms, 1 to 300 atoms, 1 to 200 atoms, 1 to 100 atoms, 1 to 50 atoms, 10 to 1000 atoms, 10 to 900 atoms, 10 to 800 atoms, 10 to 500 atoms, 10 to 400 atoms, 10 to 300 atoms, 10 to 200 atoms, 10 to 100 atoms, 10 to 50 atoms, 25 to 1000 atoms, 25 to 900 atoms, 25 to 800 atoms, 25 to 500 atoms, 25 to 400 atoms, 25 to 300 atoms, 25 to 200 atoms, 25 to 100 atoms,25 to 50 atoms, 50 to 1000 atoms, 50 to 900 atoms, 50 to to to to at least about 30,000 Daltons. In some embodiments, the linker as a molecular weight of at most about 100,000 Daltons, at most about 50,000 Daltons, at most about 40,000 Daltons, at most about 30,000 Daltons, at most about 25,000 Daltons, at most about 20,000 Daltons at most about 15,000 Daltons, at most about 10,000 Daltons, or at most about 5,000 Daltons. -95- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the linker comprises a reaction product of one or more pairs of conjugation handles and a complementary conjugation handle thereof. In some embodiments, the an of C6 , - -, , - , - - C6C6 qb- or or or or -96- 49194109.1 ES Docket No.94917-0155.737601WO wherein each is a point of attachment to the antibody or antigen binding fragment or the IL- to or , – , - - , - - , - or or - or or or or ES Docket No.94917-0155.737601WO each of qa, qb, qc and qd is independently an integer from 1-100, g is an integer from 1-100, or , , , ES Docket No.94917-0155.737601WO O n H n N OHNnH Nnn O N O NnOnN HnmHmH , , , , , 1- the ES Docket No.94917-0155.737601WO N of , , , , is 1- , , ES Docket No.94917-0155.737601WO O N H n 1- In , – - -, , - , - O- , - C6 qf- or or or or to ES Docket No.94917-0155.737601WO In some embodiments, the linking group which connects to the first point of attachment (e.g., the point of attachment to the IL-18 polypeptide) comprises poly(ethylene glycol). In some of a In , or In some embodiments, the antibody or antigen binding fragment is linked to the IL-18 polypeptide through a peptide linker. In some embodiments, the antibody or antigen binding fragment is linked to the IL-18 polypeptide as a fusion protein. In such instances, the linker comprises one or more peptide bonds between the antibody or antigen binding fragment and the IL-18 polypeptide. In some embodiments, the linker between the fusion protein of the antibody or antigen binding fragment and the IL-18 polypeptide is a bond. In some embodiments, the linker between the fusion protein of the antibody or antigen binding fragment and the IL-18 polypeptide is a linking peptide. Non-limiting examples of linking peptides include, but are not limited to (GS)n(SEQ ID NO: 424), (GGS)n (SEQ ID NO: 425), (GGGS)n (SEQ ID NO: 426), (GGSG)n (SEQ ID -102- 49194109.1 ES Docket No.94917-0155.737601WO NO: 427), or (GGSGG)n(SEQ ID NO: 428), (GGGGS)n(SEQ ID NO: 429), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For example, a linking peptide can be (GGGGS)3 (SEQ ID NO: 430) or (GGGGS)4(SEQ ID NO: 431). In some embodiments, the IL-18 polypeptide is fused to the C- terminal end of the antibody or antigen binding fragment (optionally through a linking peptide). In some embodiments, the IL-18 polypeptide is fused to the N-terminal end of the antibody or antigen binding fragment (optionally through a linking peptide). Cleavable linkers In some embodiments, the linker (e.g., a chemical or peptide linker as provided herein) is a cleavable linker. In some embodiments, the cleavable linker is cleaved at, near, or in a tumor microenvironment. In some embodiments, the tumor is mechanically or physically cleaved at, near, or in the tumor microenvironment. In some embodiments, the tumor is chemically cleaved at, near, or in a tumor microenvironment. In some embodiments, the cleavable linker is a reduction sensitive linker. In some embodiments, the cleavable linker is an oxidation sensitive linker. In some embodiments, the cleavable linker is cleaved as a result of pH at, near, or in the tumor microenvironment. In some embodiments, the cleavable linker is cleaved by a tumor metabolite at, near, or in the tumor microenvironment. In some embodiments, the cleavable linker is cleaved by a protease at, near, or in the tumor microenvironment. Act-IL-18 Polypeptides The present disclosure relates to activatable immunocytokine compositions containing activatable IL-18 (Act-IL-18) polypeptides that are useful as therapeutic agents. The Activatable IL-18 polypeptides provided herein attached to antibodies can be used as immunotherapies or as parts of other immunotherapy regimens. According to one aspect of the instant disclosure are Act- IL-18 polypeptides themselves which can be useful either as part of activatable immunocytokine compositions described herein, or for other uses. Thus, the instant disclosure expressly regards the Act-IL-18 polypeptides themselves as described herein as being a distinct aspect of the invention (i.e., in certain aspects the invention can include an Act-IL-18 polypeptide described herein independently of an activatable immunocytokine composition). In one aspect, the Act-IL-18 polypeptides of activatable immunocytokines of the disclosure comprise artificial polypeptides which are attached to an IL-18 polypeptide. An artificial polypeptide can comprise a group such as polymer or spacer used to link the artificial moiety to the IL-18 polypeptide. The artificial polypeptide comprises a cleavable group which, -103- 49194109.1 ES Docket No.94917-0155.737601WO when cleaved, releases all or a portion of the artificial polypeptide. Upon cleavage, the Act-IL-18 is converted into an active form of the IL-18 polypeptide which is capable of performing IL-18 activity. In one aspect, provided herein, is an Act-IL-18 polypeptide of an activatable immunocytokine comprising an artificial polypeptide attached to an IL-18 polypeptide. In some embodiments, the artificial polypeptide inhibits the Act-IL-18 polypeptide from interacting with and / or signaling through an IL-18 receptor. In some embodiments, the artificial polypeptide is capable of undergoing a change in response to a condition or stimulus which results in a conversion of the Act-IL-18 polypeptide into an active IL-18 polypeptide. In some embodiments, the change is a cleavage of at least a portion of the artificial polypeptide from the IL-18 polypeptide. In one aspect, an Act-IL-18 of an activatable immunocytokine of the instant disclosure is activated in or near a target tissue of a subject. In some embodiments, the Act-IL-18 is preferentially activated in or near the target tissue of a subject (e.g., activated at a higher rate in or near the target tissue compared to other tissue). In some embodiments, the Act-IL-18 is activated preferentially at or near a target tissue of the subject such that the area at or near the target tissue comprises at least 2-fold, at least 4-fold, at least 8-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold the concentration of the active form of the IL-18 polypeptide compared to non-target tissues. In some embodiments, the concentrations compared are the peak concentrations of the active form of the IL-18 polypeptide after administration of the Act-IL-18. In some embodiments, the Act-IL-18 is preferentially activated in or near disease tissue of the subject. In some embodiments, the Act- IL-18 polypeptide is preferentially activated in or near cancer tissue of the subject. In some embodiments, the Act-IL-18 polypeptide is preferentially activated in or near a tumor microenvironment. In some embodiments, the Act-IL-18 is preferentially activated in the tumor microenvironment compared to non-tumor tissue. In one aspect, provided herein, is an activatable interleukin-18 (Act-IL-18) polypeptide of an activatable immunocytokine comprising: an artificial polypeptide attached to an interleukin-18 (IL-18) polypeptide, wherein the artificial polypeptide comprises a protease cleavage site, and wherein cleavage at the protease cleavage site converts the Act-IL-18 into an active form of the IL-18 polypeptide. Artificial Polypeptides -104- 49194109.1 ES Docket No.94917-0155.737601WO In one aspect, provided herein, are artificial polypeptides attached to IL-18 polypeptides incorporated into activatable immunocytokines. Artificial polypeptides as provided herein serve to detune the activity of the IL-18 polypeptide while they are attached in an intact form. In some embodiments, cleavage of the artificial polypeptide serves to activate the IL-18 polypeptide (e.g., allowing the IL-18 polypeptide to signal through IL-18Rab). An artificial polypeptide provided herein can be attached to any residue. In some embodiments, the artificial polypeptide is an artificial polypeptide (e.g., attached to a terminal residue of the IL-18 polypeptide). In some embodiments, the artificial polypeptide can have other functionalities attached (e.g., in addition to being attached to the IL-18 polypeptide, the artificial polypeptide is also attached to another group, such as an additional polypeptide (e.g., antibody, dummy receptor, another cytokine), a half-life extension polymer (e.g., poly(ethylene glycol) (PEG)), or another desired functionality). In some embodiments, cleavage of the artificial polypeptide serves also to cleave this additional group from the IL-18 polypeptide. In one aspect, the Act-IL-18 polypeptides provided herein comprise an artificial polypeptide attached to a terminal residue of the IL-18 polypeptide. In some embodiments, the artificial polypeptide is covalently attached to the IL-18 polypeptide. In some embodiments, the artificial polypeptide is a group which is not naturally attached to the terminus of a WT IL-18 polypeptide, such as the natural precursor 36 amino acid propeptide directly attached to the WT IL-18. When the IL-18 polypeptide is a variant IL-18 polypeptide (e.g., having at least one amino acid substitution relative to WT IL-18), then the artificial polypeptide can be the natural propeptide. In some embodiments, the artificial polypeptide is engineered to possess the properties provided herein. In some embodiments, the artificial polypeptide is fused to an IL-18 polypeptide (e.g., as a fusion protein). In some embodiments, the artificial polypeptide is chemically attached to an IL-18 polypeptide, or is incorporated into an IL-18 polypeptide by synthetic means (e.g., during synthesis of an IL-18 polypeptide). In some embodiments, an artificial polypeptide provided herein inhibits at least one activity associated with an IL-18 polypeptide, such as the ability to bind to an IL-18 receptor or effectuate signaling through the IL-18 receptor (IL-18Rab) (e.g., inducing production of IFNγ in an immune cell). In some embodiments, when the artificial polypeptide is intact, the Act-IL-18 polypeptide is in an inactive state (e.g., lacks or has a substantially diminished ability to bind IL- 18Rab or signal through IL-18Rab). -105- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the presence of the intact artificial polypeptide on the IL-18 polypeptide results in the Act-IL-18 polypeptide displaying a binding affinity to IL-18Rab or an at the 18 18 In a at the specific cleavage site at a different tissue. In some embodiments, the target tissue is diseased tissue of the subject. In some embodiments, the target tissue is cancer tissue of the subject. In some embodiments, the target tissue is a tumor microenvironment. In some embodiments, the target tissue is a tumor. -106- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the protease cleavage site is positioned such that all or only a portion of the artificial polypeptide is removed from the IL-18 polypeptide after cleavage. In some embodiments, none of the artificial polypeptide is present on the IL-18 polypeptide after cleavage (e.g., only residues corresponding to residues in SEQ ID NO: 1 are present after cleavage). In some embodiments, a portion of the artificial polypeptide remains attached to the IL-18 polypeptide after cleavage. The artificial polypeptide can be attached to either the N-terminal residue or the C- terminal residue of the IL-18 polypeptide. In some embodiments, the artificial polypeptide is attached to the N-terminal residue. In some embodiments, the artificial polypeptide is attached to the N-terminal amine of the IL-18 polypeptide. In some embodiments, the artificial polypeptide is attached to the C-terminal residue. In some embodiments, the artificial polypeptide is attached to the C-terminal carboxyl of the IL-18 polypeptide. In some embodiments, the N-terminal residue is the residue closest to residue position 1 of SEQ ID NO: 1 which is present on an IL-18 polypeptide as provided herein (e.g., the first residue of SEQ ID NO: 1 which has not been truncated). In some embodiments, the N-terminal residue of the IL-18 polypeptide is the residue at a position corresponding to position 1 in SEQ ID NO: 1. In some embodiments, the N-terminal residue of the IL-18 polypeptide is Y1. In some embodiments, the N-terminal residue of the IL-18 polypeptide is Y1G. In some embodiments, the N-terminal residue of the IL-18 polypeptide is Y1M. In some embodiments, the C-terminal residue is the residue at position 157 of SEQ ID NO: 1. In some embodiments, the C-terminal residue is D157. In some embodiments, terminal residues of the IL-18 polypeptide are substituted such that the artificial polypeptide is positioned such that the entirety of the artificial polypeptide is cleaved from the IL-18 polypeptide. For example, if it is intended to introduce a cleavage site at a position corresponding to residue 1 of SEQ ID NO: 1, a protease cleavage sequence P1-P2-P3-P’1-P’2-P’3 can be selected (where the cleavage site is between P3 and P’1), and residues 1, 2, and 3 of SEQ ID NO: 1 can be substituted for P’1, P’2, and P’3 respectively, with P1-P2-P3- appended thereon. In this case, the artificial polypeptide would be considered to comprise P1-P2-P3-, with P’1, P’2, and P’3 as part of the IL-18 polypeptide (substituted residues). Examples of artificial polypeptides and their mechanisms of action are shown in FIGs.8- 13. FIG.8 depicts an artificial polypeptide affixed to a terminal residue of the IL-18 polypeptide. Also attached to the artificial polypeptide is a blocking moiety which facilitates keeping the IL-18 -107- 49194109.1 ES Docket No.94917-0155.737601WO polypeptide in an inactive state. When the artificial polypeptide is cleaved (e.g., by a tumor microenvironment protease), the entire artificial polypeptide is cleaved (revealing the terminal residue of the IL-18 polypeptide, as is the blocking moiety. The IL-18 in this example has a conjugation handle attached elsewhere to the IL-18 polypeptide, which can serve to attach an additional group (e.g., half-life extension polymer or an additional polypeptide), and it can be attached either before or after cleavage of the artificial polypeptide. FIG.9 shows a similar Act-IL-18 construct shown in in the previous figure but lacks the blocking moiety. In some instances, the presence of only a short peptide on the N-terminus can sufficiently detune the activity of the IL-18 polypeptide, and the activity can be restored upon cleavage. FIG. 10A shows a similar Act-IL-18 construct to that shown in FIG.8, but the artificial polypeptide is attached to the C-terminus. FIG. 10B shows a similar Act-IL-18 construct to that shown in FIG. 9, but the artificial polypeptide is attached to the C-terminus. FIG. 11 depicts an analogous construct to that shown in FIG. 8, but residues 1, 2, and 3 of the IL-18 polypeptide are substituted such that the artificial polypeptide is cleaved entirely (residues 1, 2, and 3, though substituted, still correspond to positions 1, 2 and 3 of SEQ ID NO: 1). FIG. 12 is analogous to FIG. 11, but the artificial polypeptide is at the C-terminus. Alternatively to substituting residues 1, 2, and 3 of the IL-18 as depicted in FIG. 11, a cleavable peptide could be selected such that natural residues 1, 2, and 3 of the IL-18 polypeptide (e.g., Y, F and G, respectively), or a subset of the natural residues, form part of the cleavage recognition site of the relevant protease such that the entire artificial polypeptide is cleaved, thus leaving an unmodified N-terminus of the IL-18 polypeptide after cleavage. For example, a sequence of -PLG- can be appended the N-terminal Y of the IL-18 polypeptide to allow complete cleavage of the artificial polypeptide by a matrix metalloprotease. Additionally, in such a case, the N-terminal residue or set of residues (e.g., residues 1, 2, and / or 3) can be substituted relative to SEQ ID NO: 1 in order to optimize cleavage efficiency of the cleavage site. Such an approach could also be adopted at the C-terminus of the IL-18 polypeptide. FIG.13 depicts an Act-IL-18 polypeptide comprising an artificial polypeptide which has a conjugation handle attached to it such that cleavage of the artificial polypeptide will also cleave the conjugation handle (or anything which has been attached to the conjugation handle) from the -108- 49194109.1 ES Docket No.94917-0155.737601WO IL-18 polypeptide. By way of non-limiting example, such a construct could be used to conjugate an antibody to the IL-18 polypeptide. Such a construct could be used to tissue specifically deliver an IL-18 polypeptide, then also activate it at the desired site through cleavage at the target tissue. In some embodiments, cleavage at the protease cleavage site leaves no amino acid residues attached to the IL-18 polypeptide. In some embodiments, cleavage at the protease cleavage site leaves at least 1 amino acid residue attached to the IL-18 polypeptide. In some embodiments, cleavage at the protease cleavage site leaves at most 1, 2, 3, 4, or 5 amino acid residues attached to the IL-18 polypeptide. In some embodiments, cleavage at the protease cleavage site leaves 1, 2, 3, 4, or 5 amino acid residues attached to the IL-18 polypeptide. In some embodiments, cleavage at the protease cleavage site leaves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid residues attached to the IL-18 polypeptide. In some embodiments, an Act-IL-18 can optionally contain a tag used for expression and / or purification of a recombinant Act-IL-18 as provided herein. The tag can be situated upstream of an N-terminal artificial polypeptide or downstream of a C-terminal artificial polypeptide. The tag may be removed (e.g., enzymatically) prior to final formulation and / or administration to a subject. Exemplary tags include a HIS6 (HHHHHH, SEQ ID NO: 687), a Strep Tag (WSHPQFEK (SEQ ID NO: 688) or AWAHPQPGG (SEQ ID NO: 689), or a chitin binding tag (TTNPGVSAWQVNTAYTAGQLVTYNGKTYKCLQPHTSLAGWEPSNVPALWQLQ, SEQ ID NO: 87). The artificial polypeptide can be cleaved by a protease. In some embodiments, the artificial polypeptide contains a protease cleavage site that can be cleaved specifically by one or more proteases. In some embodiments, the protease cleavage site can be cleaved at a site preferred by one or more proteases. In some embodiments, the protease is found at higher concentrations and / or demonstrates higher proteolytic activity at or near a target tissue of a subject. In some embodiments, the target tissue is disease tissue. In some embodiments, the target tissue is a cancer. In some embodiments, the target tissue is a tumor microenvironment. In some embodiments, the protease is found at higher concentrations and / or demonstrates higher proteolytic activity at or near the tumor microenvironment relative to non-tumor tissue. In some embodiments, the protease is found at higher concentrations at or near the tumor microenvironment relative to non-tumor tissue. In some embodiments, the protease demonstrates -109- 49194109.1 ES Docket No.94917-0155.737601WO higher proteolytic activity at or near the tumor microenvironment relative to non-tumor tissue. In some embodiments, the protease is selected from kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, proteinase 3 (PR-3), granzyme M, a calpain, a matrix metalloproteinase (MMP), a disintegrin and metalloproteinase (ADAM), a fibroblast activation protein alpha (FAP), a plasminogen activator, a cathepsin, a caspase, a tryptase, and a tumor cell surface protease. In some embodiments, the cleavable peptide is cleavable by a protease selected from a kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, proteinase 3 (PR-3), granzyme M, a calpain, a matrix metalloproteinase (MMP), a disintegrin and metalloproteinase (ADAM), a fibroblast activation protein alpha (FAP), a plasminogen activator, a cathepsin, a caspase, a tryptase, a matriptase, and a tumor cell surface protease, or any combination thereof. In some embodiments, the protease is selected from kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, proteinase 3 (PR- 3), granzyme M, urokinase plasminogen activator (uPA), a calpain, a matrix metalloproteinase (MMP), a disintegrin and metalloproteinase (ADAM), a fibroblast activation protein alpha (FAP), a matriptase, a plasminogen activator, a cathepsin, a caspase, a tryptase, and a tumor cell surface protease. In some embodiments, the cleavable peptide is cleavable by a protease selected from a kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, proteinase 3 (PR-3), urokinase plasminogen activator (uPA), granzyme M, a calpain, a matrix metalloproteinase (MMP), a disintegrin and metalloproteinase (ADAM), a fibroblast activation protein alpha (FAP), a matriptase, a plasminogen activator, a cathepsin, a caspase, a tryptase, a matriptase, and a tumor cell surface protease, or any combination thereof. In some embodiments, the protease is urokinase plasminogen activator (uPA) or matriptase. In some embodiments, the cleavable peptide is cleavable by urokinase plasminogen activator (uPA) or matriptase. In some embodiments, the protease is a protease selected from the Table below. Tissue / Tumor specific proteases Protease Specificity Other Aspects Secreted by CD8+Cytotoxic T cells Granzyme B (grB) Cleaves after Asp Type of serine protease; Strongly implicated in inducing perforin-dependent target cell apoptosis Granzyme A (grA) trypsin-like, cleaves after basic Type of serine protease. residues Granzyme H (grH) Unknown substrate specificity Type of serine protease; Other granzymes are also secreted by killer T cells, but not all are present in humans -110- 49194109.1 ES Docket No.94917-0155.737601WO Caspase-8 Cleaves after Asp residue Type of cysteine protease; plays and essential role in TCR-induced cellular expansion. Mucosa-associated Cleaves after Arg residues Type of cysteine protease; likely acts both lymphoid tissue as a scaffold and proteolytically active (MALT1) enzyme in the CBM-dependent signaling pathway. Tryptase Target: angiotensin I, Type of mast cell-specific serine protease; fibrinogen, prourokinase, trypsin-like; resistant to inhibition by TGFβ; preferentially cleaves macromolecular protease inhibitors proteins after lysine or expressed in mammals due to their arginine residues. tetrameric structure, with all sites facing narrow central pore; also associated with inflammation. Associated with Inflammation: Thrombin Targets: FGF-2 Type of serine protease; modulates activity of vascular growth factors, chemokines HB-EGF, Osteo-pontin, and extracellular proteins; strengthens PDGF, VEGF VEGF-induced proliferation; induces cell migration; angiogenic factor; regulates hemostasis Chymase Exhibit chymotrypsin-like Type of mast cell-specific serine protease. specificity, cleaving proteins after aromatic amino acid residues. Carboxypeptidase A Cleaves amino acid residues Type of zinc-dependent metalloproteinase (MC-CPA) from C-terminal end of peptides and proteins Kallikreins Targets: high molecular Type of serine protease; modulate weight kininogen, pro- relaxation response; contribute to urokinase inflammatory response; activates pro- apoptotic signaling Elastase Targets: E-cadherin, GM-CSF, Type of neutrophil serine protease; IL-1, IL-2, IL-6, IL-8, degrades ECM components; regulates p38MAPK, TNFα, VE-cadherin. inflammatory response; activates pro- apoptotic signaling. Cathepsin G Targets: ENA-78, IL-8, MCP- Type of serine protease; degrades ECM 1, MMP-2, MT1-MMP, PAI- components; chemo-attractant of 1, RANTES, TGFβ, TNFα leukocytes; regulates inflammatory response; promotes apoptosis. PR-3 Targets:ENA-78, IL-8, IL-18, Type of serine protease; promotes JNK, p38MAPK, TNFα inflammatory response; activates pro- apoptotic signaling. Granzyme M (GrM) Cleaves after Met and other Type of serine protease; only expressed in long, unbranched hydrophobic NK cells. residue. Calpains Cleave between Arg and Gly Family of cysteine proteases; calcium- dependent; activation is involved in the process of numerous inflammation- associated diseases. -111- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the protease cleavage site is comprised within a protease recognition sequence. The protease recognition sequence can be recognized and cleaved by the protease. In some embodiments, the protease recognition sequence is a natural peptide sequence which has been incorporated into the artificial polypeptide. In some embodiments, the protease recognition sequence is a synthetic (e.g., man-made, designed, or engineered) sequence. In some embodiments, the protease recognition sequence comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a sequence set forth in Table 2A. Table 2A – Protease specific protease recognition sequences SEQ ID NO: Protease Protease recognition sequences 501 MMP7 KRALGLPG 502 MMP9 PR(S / T)(L / I)(S / T) 503 MMP9 LEATA 504 MMP11 GGAANLVRGG 505 MMP14 SGRIGFLRTA 506 MMP PLGLAG 507 MMP PLGLAX 508 MMP ESPAYYTA 509 MMP RLQLKL 510 MMP RLQLKAC 511 Urokinase SGRSA plasminogen activator (uPA) 512 uPA DAFK 513 uPA GGGRR 514 Lysosomal Enzyme GFLG 515 Lysosomal Enzyme ALAL 516 Lysosomal Enzyme FK 517 CathepsinB NLL 518 CathepsinD GLLYA 519 Cathepsin K GGPRGLPG 520 Prostate Specific HSSKLQ Antigen 521 Prostate Specific HSSKLQL Antigen -112- 49194109.1 ES Docket No.94917-0155.737601WO 522 Prostate Specific HSSKLQEDA Antigen 523 Thrombin DPRSFL 524 Thrombin PPRSFL 525 Caspase-3 DEVD 526 Caspase-3 DEVDP 527 Caspase-3 KGSGDVEG 528 Interleukin 1P GWEHDG converting enzyme 529 FAP KQEQNPGST 530 Kallikrein 2 GKAFRR 531 Plasmin DAFK 532 Plasmin DVLK 533 Plasmin DAFK 534 TOP ALLLALL 100 MMP9 (also referred SGGPGPAGMKGLPG to herein as Linker X) 101 MMP9 SGGPGPAGMKGLPGS 102 MMP2-7-9-14 + EAGRSANHEPLGLVAT matriptase + uPA + Legumain 103 MMP9 + matriptase PQASTGRSGG + uPA 104 MMP9 + matriptase PQGSTGRAAG + uPA 105 MMP9 + matriptase PPASSGRAGG + uPA 106 MMP7-9-10 RSGVPLSLYSGSGGGK 107 MMP7-9-10 RSGMPYDLYHPSGK 108 MMP7-9-10 RGPDSGGFMLTSGK 109 MMP7-9-10 RGSGHEQLTVSGGSK 110 MMP7-9-10 RSGRAAAVKSPSGK 111 MMP7-9-10 RGSGISSGLLSGRSDNHSGK 112 MMP7-9-10 RGDLLAVVAASGGK 113 MMP7-9-10 RGGISSGLLSGRSGK 114 Meprin A / B SGGGKKLADEPEGGS 115 Meprin A / B (High GGGKFLADEPEGG Efficiency) 116 Cathepsin S, K, L ARLQSAAP 117 Cathepsin S + MMP9 ARLQSAAPAGLKGA + Meprin A 118 MMP9 (High GSGGPGPAGMHGLPGGS Efficiency) -113- 49194109.1 ES Docket No.94917-0155.737601WO 119 uPA GGGSHTGRSAYFGGGS 120 MMP9-2 SGGPGPAGLKGAPGS 121 MMP2-7-9 VPLSLYSG 122 uPA + Matriptase + SGLLSGRSDNH legumain 123 uPA SGRSDNIGGGS 124 MMP-14 + uPA LQESLRSKESGRSDI 125 uPA ISSGLLSGRSDNH 126 uPA LSGRSDDH 127 uPA ISSGLLSGRSDQH 128 uPA ISSGLLSGRSDNI 129 MMP2-7-9 PLGLAG 130 MMP GPAGMKGL 131 MMP LSGRSDQH 132 MMP LSGRSDNI 133 MMP ISSGLLSGRSDNH 134 MMP GPLGVRG 135 MMP GPLGLAR 136 MMP GPAALVGA 137 MMP GPAALIGG 138 MMP GPLNLVGR 139 MMP GPAGLVAD 140 MMP GPANLVAP 141 MMP VPLSLYSG 142 MMP SGESPAYYTA 143 MMP GGPRGLG 144 MMP HSSKLQ 145 MMP HSSKLQL 146 MMP7 KRALGLPG 147 MMP9 LEATA 148 MMP11 GGAANLVRGG 149 MMP14 SGRIGFLRTA 150 MMP PLGLA 151 MMP ESPAYYTA 152 MMP RLQLKL 153 MMP RLQLKAC 154 uPA SGRSA 155 uPA (D-Ala)FK 156 uPA GGGRR 157 Lysosomal Enzyme GFLG 158 Prostate Specific HSSKLQEDA Antigen -114- 49194109.1 ES Docket No.94917-0155.737601WO 159 HSV Protease LVLASSSFGY 160 HIV Protease GVSQNYPIVG 161 CMV Protease GVVQASCRLA 162 Thrombin DPRSFL 163 Thrombin PPRSFL 164 Caspase-3 DEVD 165 Caspase-3 DEVDP 166 Caspase-3 KGSGDVEG 167 Interleukin 1β GWEHDG converting enzyme 168 Enterokinase EDDDDKA 169 FAP KQEQNPGST 170 Kallikrein 2 GKAFRR 171 Plasmin DAFK 172 Plasmin DVLK 173 Plasmin DAFK 174 TOP ALLLALL 175 MMP A3 SGAKPRALTA 176 MMP B49 SGLRLAAITA 177 MMP B74 SGESLAYYTA 178 MMP B74P SGESPAYYTA 179 MMP B74R SGESLRYYTA 180 MMP C9 SGRSLSRLTA 181 MMP C9R SGRSLRRLTA 182 MMP A13 SGAVSWLLTA 183 MMP A13P SGAPSWLLTA 184 MMP A13R SGAVRWLLTA 185 MMP B37 SGANISDLTA 186 MMP A34 SGNRYSSLTA 187 MMP A21 / SGHMHKALTA MMPA21A 190 MMP GEEGEEPLGLAG 191 MMP GPLGLAG 192 EAGRSANHTPAGLTGP 193 GEAGRSANHTPAGLTGP 194 MMP (partial PLG sequence) In some embodiments, the protease recognition sequence comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at -115- 49194109.1 ES Docket No.94917-0155.737601WO least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to a sequence set forth in Table 2B. Table 2B – Protease Cleavage Sequences SEQ ID NO Sequence 101 SGGPGPAGMKGLPGS 601 SSRGPASNRRLPLGLAG 602 SSRAVFRKNLGPLGLAG 603 SGRVLRKAGPQPLVD 604 SGRVLTLRKAPWGLLE 605 SGRVLGPAGLVG 606 SGRVLGPANLVG 607 SGRVLPAGLVG 608 SGRVLGPLNLSG 609 RQRRSAPLGLAG 610 RQRRSPLGLAG 611 SGRVLTLRKAGPAGLVG 612 SGRVLTLRKAGPANLVG 613 SGRVLRKAGPAGLVG 614 SGRVLRKAGPANLVG 615 SGRVLPANLVG 616 SGRVAGLVG 617 SGRVANLVG 618 PASNRRLPLGLAG 619 SSRVFRKPANLAG 620 SGRVLTLRKAALPLAM 621 SSRGRRGPYMLQG 622 SSRGPYMLQG 623 SGRVLPLGMRA 624 SGRVLPYAMTA 625 KWGKSAPLGLAG 626 RYGKSAPLGLAG 627 RQRRSAAPLGLAG 628 RQRRSVVGG 629 SPLGLAGS 630 RGRKVANLVG 631 RQRKVANLVG 632 RGRRVANLVG -116- 49194109.1 ES Docket No.94917-0155.737601WO 633 RGRKSPANLVG 634 RGRKPYMLQG 635 RGRKSPYMLQG 636 RGRKPQPLVD 637 RGRKSPQPLVD 638 RGRKSQPLVD 639 SGRVAPYMLQG 640 SGRVYMLQG 641 SGRVAPQPLVD 642 SGRVQPLVD 643 RGRRGP 644 PLGLAG 645 PLG 646 SGRVANLVG 647SGRVANLVGGSG 648 RGRRVANLVG 649 RGRRVANLVGGSG 650 SGRVAN 651 RGRRVAN 652 SGRPLG 653 RGRRPLG 654 SGRPLGLAG 655 RGRRPLGLAG 656 RGRRVANPLGLAG 657 RGRRVANPLGLAGSG 658 RGRRPLGLAGGSG 659 RGRRVANPLG 660 RGRRVANPLGGSG 661RGRRSGRVANPLG 662RGRRSGRAANLVRPLGLAG 663AANLVR664RGRRSGRAANLVRPLG 665RGRRAANLVRPLG 666RGRRAANLVRPLGLAG 667RGRRAANLVR 668RGRRSGRAANLVR 669HSSKLQ670RGRRHSSKLQ -117- 49194109.1 ES Docket No.94917-0155.737601WO 671RGRRSGRHSSKLQ 672RGRRHSSKLQPLG 673RGRRSGRHSSKLQPLG 674RGRRHSSKLQVAN 675RGRRSGRHSSKLQVAN 676 SGRVANPLGLAG 677 SGRVANPLGLAGSG 678 SGRPLGLAGGSG 679 SGRVANPLG 680 SGRVANPLGGSG 681SGRAANLVRPLG 682SGRAANLVRPLGLAG 683SGRAANLVR684SGRHSSKLQ685SGRHSSKLQPLG 686SGRHSSKLQVAN In some embodiments, cleavage of the protease cleavage site leaves no amino acid residues attached to the IL-18 In such cases, the can of in 1 ES Docket No.94917-0155.737601WO site leaves at most 1, 2, 3, 4, or 5 amino acid residues attached to the IL-18 polypeptide. In some embodiments, cleavage of the protease cleavage site leaves 1, 2, 3, 4, or 5 amino acid residues attached to the IL-18 polypeptide. In some embodiments, cleavage of the protease cleavage site leaves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid residues attached to the IL-18 polypeptide. In some embodiments, cleavage of the protease cleavage site leaves at most 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residues attached to the IL-18 polypeptide. Further exemplary protease recognition sequence, such as cleavable peptide sequences which can be incorporated into an Act-IL-18 polypeptide as provided herein can be found in any one of U.S. Patent Publication Nos: US2010 / 0189651, US2016 / 0289324, US2018 / 0125988, US2019 / 0153115, US2020 / 0385469, US2021 / 0260163, US2022 / 0048949, US2022 / 0267400, US2021 / 0115102, US2022 / 0002370, US2021 / 0163562, US20200392235, US2021 / 0139553, US2021 / 0317177, US2020 / 0283489, US2021 / 0002343, US2021 / 0292421, US2021 / 0284728, US2021 / 0269530, US2022 / 0054544, US2021 / 0355219, US2022 / 0073613, US2021 / 0047406, and / or Patent Cooperation Treaty Publication Nos: WO2021 / 202675, WO2021 / 062406, WO2021 / 142471, WO2021 / 216468, WO2021 / 119516, WO2021 / 253360, WO2021 / 146455, WO2021 / 202678, WO2021 / 202673, WO2021 / 189139, WO2020 / 232303, WO2022 / 115865, WO2021 / 202678, and / or Chen et. al., J Bio Chem, 277, V6 P4485-4491 (2002). Further examples of cleavable peptide sequences compatible with the instant disclosure are described in Patent Cooperation Treaty Publication No. WO2024 / 150172. Blocking Moieties In some embodiments, the artificial polypeptide comprises a blocking moiety. In some embodiments, the blocking moiety is a group which, when attached to the IL-18 polypeptide in the Act-IL-18 polypeptide, acts to disrupt or inhibit binding of the IL-18 polypeptide with the IL- 18 receptor or a subunit thereof (e.g., as measured by experiments designed to detect binding, or by in vitro or in vivo activity analysis of the Act-IL-18 polypeptide). In some embodiments, the blocking moiety is a steric blocking group or a specific blocking group. In some embodiments, the blocking moiety is a steric blocking group. In some embodiments, a steric blocking group has no specific interaction with the IL-18 polypeptide, but its presence hinders the interaction of the Act-IL-18 polypeptide with the receptor owing to its bulk. In some embodiments, the steric blocking group is a polymer (e.g., polyethylene glycol) or a polypeptide (e.g., albumin, an Fc region, etc.). -119- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the blocking moiety is a specific blocking group. In some embodiments, the specific blocking group has a specific binding or other interaction to IL-18. Non- limiting examples of specific blocking groups can include IL-18 propeptides, antibodies or antigen binding fragments which bind IL-18, IL-18 receptor subunits or domains or other fragments thereof, IL-18 binding proteins or fragments thereof, or other groups capable of specific binding to IL-18. In some embodiments, the blocking moiety is a propeptide of IL-18, or a variant thereof. In some embodiments, the blocking moiety is a propeptide of IL-18. Endogenously, human IL-18 is expressed as an immature, inactive 193 amino acid having the sequence MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLNDQVLFIDQ GNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKE MNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELG DRSIMFTVQNED (SEQ ID NO: 88), the first 36 amino acids of which are a propeptide which is cleaved by caspases to yield the mature, active form of IL-18 (SEQ ID NO: 1). In some embodiments, the blocking moiety is attached to the N-terminus of the IL-18 polypeptide (e.g., through a cleavable peptide comprising the specific cleavage site and any optional linker peptides), and the blocking moiety is a propeptide of IL-18. In some embodiments, the blocking moiety is a human IL-18 propeptide or a variant thereof. In some embodiments, the blocking moiety is an IL- 18 propeptide an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO: 89. In some embodiments, the blocking moiety is an IL-18 propeptide having a sequence at least 95% identical to the sequence set forth in SEQ ID NO: 89. In some embodiments, the blocking moiety is an IL- 18 propeptide comprising the sequence set forth in SEQ ID NO: 89. In some embodiments, the blocking moiety is an IL-18 propeptide comprising the sequence set forth in SEQ ID NO: 89 with a substitution for residue C10 (e.g., a C10S substitution (SEQ ID NO: 90) or a C10A substitution (SEQ ID NO: 91). In some embodiments, the IL-18 propeptide comprises one or more modifications (e.g., amino acid substitutions) which reduce the affinity of the IL-18 propeptide for the IL-18 polypeptide in the Act-IL-18 polypeptide. In some embodiments, the blocking moiety is an IL-18 propeptide, and the protease cleavage site of the Act-IL-18 polypeptide is different from that of the endogenous propeptide (i.e., the specific cleavage site is not the bond between D36 and Y37 of SEQ ID NO: 88). In some embodiments, the IL-18 propeptide acting as a blocking moiety -120- 49194109.1 ES Docket No.94917-0155.737601WO is connected to the N-terminus of the IL-18 polypeptide in the Act-IL-18 polypeptide through another protease recognition sequence (and optionally one or more linking peptides). In some embodiments, the blocking moiety is a modified IL-18 propeptide (e.g., human IL-18 propeptide) directly attached to the N-terminus of the IL-18 polypeptide. In some embodiments, the modified IL-18 propeptide comprises modifications which change the natural caspase cleavage site of SEQ ID NO: 88 to a site cleaved by another protease (e.g., any of the proteases provided herein, such as a matrix metalloprotease). In some embodiments, the three C- terminal amino acids of the IL-18 propeptide are substituted to –PLG (e.g., SEQ ID NOs: 91, 96, and 97). In some embodiments, the IL-18 propeptide comprises the –PLG substitution and at least one of the first 3 residues of the IL-18 polypeptide is substituted relative to SEQ ID NO: 1 to make a complete protease recognition sequences. Exemplary IL-18 Propeptide Sequences SEQ ID Blocking Moiety Sequence 89 MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESD 90 MAAEPVEDNSINFVAMKFIDNTLYFIAEDDENLESD 91 MAAEPVEDNAINFVAMKFIDNTLYFIAEDDENLESD 92 MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLPLG 96 MAAEPVEDNSINFVAMKFIDNTLYFIAEDDENLPLG 97 MAAEPVEDNAINFVAMKFIDNTLYFIAEDDENLPLG In some embodiments, an Act-IL-18 polypeptide comprising a human IL-18 propeptide or variant thereof as a blocking moiety exhibits substantially reduced activity compared to the IL- 18 polypeptide by itself or the activated form of the IL-18 polypeptide (e.g., substantially no activity, or activity which is reduced by more than 1000-fold). In some embodiments, it may be desirable for the Act-IL-18 with an IL-18 propeptide attached to retain a greater activity prior to activation. In order to accomplish this, in some embodiments, it may be advantageous to use an IL-18 propeptide from a non-human species. In some embodiments, an Act-IL-18 polypeptide provided herein comprises an IL-18 propeptide from a non-human species. In some embodiments, the non-human species is a mammal. In some embodiments, the non-human species is a primate, a rodent, an equine, a bovine, an ursine, a porcine, an equine, a chiroptera, a camelid, or other -121- 49194109.1 ES Docket No.94917-0155.737601WO animal. In some embodiments, the non-human IL-18 propeptide has an amino acid sequence which is at least 50%, 60%, 70%, or 75% identical to that of SEQ ID NO: 89. In some embodiments, the blocking moiety comprises a portion (e.g., a domain or portion thereof) of an IL-18 receptor subunit, or a variant thereof. In some embodiments, the blocking moiety comprises a portion (e.g., a domain or portion thereof) of an IL-18 receptor subunit, or a variant thereof, and the blocking moiety is connected to the C-terminus of the IL-18 polypeptide in the Act-IL-18 polypeptide. In some embodiments, the portion of the IL-18 receptor subunit or variant thereof is attached to the C-terminus of the IL-18 polypeptide in the Act-IL-18 polypeptide (e.g., through a cleavable peptide comprising the specific cleavage site and any optional linker peptides). In some embodiments, the blocking moiety comprises a portion of the IL-18 receptor alpha subunit or the IL-18 receptor beta subunit, or a variant thereof. In some embodiments, the blocking moiety comprises a portion of the IL-18 receptor alpha subunit or a variant thereof. In some embodiments, the blocking moiety comprises a domain of the IL-18 receptor alpha subunit or a variant thereof. In some embodiments, the blocking moiety comprises an extracellular domain, or a variant thereof, of the IL-18 receptor alpha subunit. In some embodiments, the blocking moiety comprises the D1, D2, or D3 domain, or a variant thereof, of the IL-18 receptor alpha subunit. In some embodiments, the blocking moiety comprises the D3 domain, or a variant thereof, of the IL-18 receptor alpha subunit. The sequence of the human D3 domain of the IL-18 receptor alpha subunit is shown in SEQ ID NO: 93 below. In some embodiments, the blocking moiety comprises an amino acid sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO: 93. In some embodiments, the blocking moiety comprises an amino acid sequence having at least 95% sequence identity to the sequence set forth in SEQ ID NO: 93. In some embodiments, the blocking moiety comprises the sequence set forth in SEQ ID NO: 93. In some embodiments, the blocking moiety D3 domain of the IL-18 receptor alpha subunit comprises substitutions which remove glycosylation sites from the D3 domain (e.g., N to D substitutions, as in SEQ ID NO: 94). In some embodiments, the blocking moiety comprises the amino acid sequence set forth in SEQ ID NO: 94 below. In some embodiments, the cysteines are substituted for another amino acid (e.g., A or S) in the blocking moiety (e.g., in SEQ ID NO: 93 or 94). In some embodiments, the blocking moiety comprises an amino acid sequence set forth in the table below (e.g., 98 or 99, which contain -122- 49194109.1 ES Docket No.94917-0155.737601WO substitutions to remove cysteine residues to facilitate site specific conjugation to the antibody or antigen binding fragment). SEQ ID Blocking Moiety Sequence 93 SNIVPVLLGPKLNHVAVELGKNVRLNCSALLNEEDVIYW MFGEENGSDPNIHEEKEMRIMTPEGKWHASKVLRIENIGE SNLNVLYNCTVASTGGTDTKSFILVRKAD 94 SNIVPVLLGPKLNHVAVELGKNVRLDCSALLNEEDVIYW MFGEEDGSDPNIHEEKEMRIMTPEGKWHASKVLRIENIGE SNLNVLYDCTVASTGGTDTKSFILVRKAD 98 SNIVPVLLGPKLNHVAVELGKNVRLNSSALLNEEDVIYW MFGEENGSDPNIHEEKEMRIMTPEGKWHASKVLRIENIGE SNLNVLYNSTVASTGGTDTKSFILVRKAD 99 SNIVPVLLGPKLNHVAVELGKNVRLDASALLNEEDVIYW MFGEEDGSDPNIHEEKEMRIMTPEGKWHASKVLRIENIGE SNLNVLYDATVASTGGTDTKSFILVRKAD In some embodiments, it may be desirable to introduce one or more substitutions of amino acids to the sequence of the D3 domain of the IL-18 receptor alpha subunit when used as a blocking moiety in order to enhance or detune the binding of the D3 domain to the IL-18 polypeptide in the Act-IL-18 polypeptide. In some embodiments, the substitutions can act to improve the affinity to IL-18 (enhanced attenuation of IL-18 activity) or decrease the affinity to IL-18 (greater attenuation of IL-18 activity). The full length human IL-18 receptor alpha subunit has the sequence MNCRELPLTLWVLISVSTAESCTSRPHITVVEGEPFYLKHCSCSLAHEIETTTKSWYKSSG SQEHVELNPRSSSRIALHDCVLEFWPVELNDTGSYFFQMKNYTQKWKLNVIRRNKHSCF TERQVTSKIVEVKKFFQITCENSYYQTLVNSTSLYKNCKKLLLENNKNPTIKKNAEFEDQ GYYSCVHFLHHNGKLFNITKTFNITIVEDRSNIVPVLLGPKLNHVAVELGKNVRLNCSAL LNEEDVIYWMFGEENGSDPNIHEEKEMRIMTPEGKWHASKVLRIENIGESNLNVLYNCT VASTGGTDTKSFILVRKADMADIPGHVFTRGMIIAVLILVAVVCLVTVCVIYRVDLVLFY RHLTRRDETLTDGKTYDAFVSYLKECRPENGEEHTFAVEILPRVLEKHFGYKLCIFERDV VPGGAVVDEIHSLIEKSRRLIIVLSKSYMSNEVRYELESGLHEALVERKIKIILIEFTPVTDF -123- 49194109.1 ES Docket No.94917-0155.737601WO TFLPQSLKLLKSHRVLKWKADKSLSYNSRFWKNLLYLMPAKTVKPGRDEPEVLPVLSES (SEQ ID NO: 95) (UniProt ID: Q13478). Linking Peptides In some embodiments, the artificial polypeptide comprises one or more linking peptides. In some embodiments, the linking peptide of an artificial polypeptide is positioned between the protease cleavage site and the IL-18 polypeptide (i.e., the linking peptide remains attached to the IL-18 polypeptide after cleavage) or is positions between the protease cleavage site and a blocking moiety, or both (e.g., the Act-IL-18 polypeptide has two linking peptides). In some embodiments, a linking peptide comprises from 1 to 50 amino acid, from 1 to 40 amino acids, from 1 to 30 amino acids, from 1 to 25 amino acids, from 1 to 20 amino acids, from 1 to 15 amino acids, from 1 to 10 amino acids, or from 1 to 5 amino acids. In some embodiments, the linking peptide comprises from 1 to 15 amino acids. In some embodiments, the linking peptide consists of amino acids glycine and serine. In some embodiments, the linking peptide consists of glycines. Non-limiting examples of a linking peptide include, but are not limited to (GS)n (SEQ ID NO: 424), (GGS)n (SEQ ID NO: 425), (GGGS)n (SEQ ID NO: 426), (GGSG)n (SEQ ID NO: 427), or (GGSGG)n (SEQ ID NO: 428), (GGGGS)n (SEQ ID NO: 429), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For example, a linking peptide can be (GGGGS)3 (SEQ ID NO: 430) or (GGGGS)4 (SEQ ID NO: 431). Additional linking peptides can include GGGGSGGGGSGGGG (SEQ ID NO: 432). In embodiments where the artificial polypeptide comprises multiple linking peptides, each linking peptide can be the same or different. Molecule Orientations Act-IL-18 polypeptides of activatable immunocytokines provided herein can have a variety of orientations. In some embodiments, an Act-IL-18 polypeptide provided herein comprises an orientation according to any one of the below formulas: (a) IL-18-CS; (b) IL-18-LP1-CS; (c) IL-18 – LP1-CS-LP2-BM; (d) IL-18-CS-LP1-BM; (e) IL-18-CS-BM; (f) IL-18-LP1-CP-BM; (g) BM-CS-IL-18; -124- 49194109.1 ES Docket No.94917-0155.737601WO (h) BM-LP1-CS-IL-18; (i) BM-LP1-CS-LP2-IL-18; (j) BM-CS-LP1-IL-18; (k) CS-LP1-IL-18; and (l) CS-IL-18; wherein IL-18 is the IL-18 polypeptide, CS is a moiety comprising the specific cleavage site (e.g., a protease recognition sequence), LP1is a first linking peptide, LP2is a second linking peptide, and BM is a blocking moiety, and wherein the orientations are shown in an N- terminal to C-terminal order. In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (a). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (b). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (c). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (d). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (e). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (f). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (g). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (h). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (i). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (j). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (k). In some embodiments, the Act-IL-18 polypeptide comprises the orientation of formula (l). In the orientations described above, it is expressly contemplated herein that the IL-18 polypeptide can be any of the IL-18 polypeptides described herein, the CS moiety can be any of the cleavage sequences described herein (e.g., any of those in Table 2A or Table 2B, or one having a specific sequence identity thereto, or another cleavage sequence as described herein), the blocking moieties can be any of the blocking moieties described herein (e.g., any of the IL-18 propeptides as described herein), and the linking peptides can be any of the linking peptides described herein, independently of any of the other components. In certain preferred embodiments, the Act-IL-18 polypeptides as described herein are of the formula (g) BM-CS-IL-18. In some embodiments, the blocking moiety is an IL-18 propeptide as described herein (e.g., any of the IL-18 propeptides described herein, including any of the -125- 49194109.1 ES Docket No.94917-0155.737601WO variants described herein). In some embodiments, the CS group is one of the cleavage sequence described herein (e.g., any of those in Table 2A or Table 2B, or any variant thereof described herein). In some embodiments, the IL-18 polypeptide is any on of those described herein (e.g., any one of those set forth in SEQ ID NOs: 1-86, or another IL-18 variant polypeptide described herein). IL-18 Polypeptides The Act-IL-18 polypeptides of activatable immunocytokines herein comprise IL-18 polypeptides. An IL-18 polypeptide of the constructs of the instant disclosure can contain a number of modifications to WT IL-18 (SEQ ID NO: 1), including without limitation amino acid substitutions, deletions, additions, or attachment of polymer moieties. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence set forth in any one of SEQ ID NOs: 2-67. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence set forth in any one of SEQ ID NOs: 79-83. In some embodiments, the IL-18 polypeptide comprises an amino acid sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence set forth in any one of SEQ ID NOs: 84-86. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 79. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 80. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 81. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 82. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 83. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 84. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the IL-18 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 86. Amino Acid Substitutions of IL-18 Polypeptides -126- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the IL-18 polypeptide of an Act-IL-18 polypeptide described herein comprises a polypeptide of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 at least 9, or more substitutions at one or more amino acid residues, whereas the positions of the substitutions are relative to positions in IL-18 of SEQ ID NO:1. In some embodiments, the IL-18 polypeptide comprises 1 to 9 amino acid substitutions. In some embodiments, the Act-IL-18 polypeptide comprises 1 or 2 amino acid substitutions, 1 to 3 amino acid substitutions, 1 to 4 amino acid substitutions, 1 to 5 amino acid substitutions, 1 to 6 amino acid substitutions, 1 to 7 amino acid substitutions, 1 to 8 amino acid substitutions, 2 to 3 amino acid substitutions, 2 to 4 amino acid substitutions, 2 to 5 amino acid substitutions, 2 to 6 amino acid substitutions, 2 to 7 amino acid substitutions, 2 to 8 amino acid substitutions, 2 to 9 amino acid substitutions 3 or 4 amino acid substitutions, 3 to 5 amino acid substitutions, 3 to 6 amino acid substitutions, 3 to 7 amino acid substitutions, 3 to 9 amino acid substitutions, 4 or 5 amino acid substitutions, 4 to 6 amino acid substitutions, 4 to 7 amino acid substitutions, 4 to 9 amino acid substitutions, 5 or 6 amino acid substitutions, 5 to 7 amino acid substitutions, 5 to 9 amino acid substitutions, 6 or 7 amino acid substitutions, 6 to 9 amino acid substitutions, or 7 to 9 amino acid substitutions. In some embodiments, the IL-18 polypeptide comprises 3 amino acid substitutions, 4 amino acid substitutions, 5 amino acid substitutions, 6 amino acid substitutions, 7 amino acid substitutions, or 9 amino acid substitutions. In some embodiments, the IL-18 polypeptide comprises up to 20, up to 19, up to 18, up to 17, up to 16, up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, or up to 8 amino acid substitutions to the sequence set forth in SEQ ID NO: 1. Unless specifically mentioned otherwise, the amino acid substitutions provided in this paragraph, and elsewhere in this disclosure, is with respect to SEQ ID NO: 1, as a reference sequence. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue Y1. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide can comprises Y1M substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue F2. In certain embodiments, the IL- 18 polypeptide of the Act-IL-18 polypeptide can comprises F2A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue E6. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises E6K substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide -127- 49194109.1 ES Docket No.94917-0155.737601WO comprises E6R substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue K8. In certain embodiments, the IL-18 polypeptide 18 at 18 the at 18 18 In the at 18 the 18 ES Docket No.94917-0155.737601WO In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue D54. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises D54A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue S55. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises S55A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises S55T substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises S55H substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises S55R substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue T63. In certain embodiments, the IL-18 polypeptide of the Act- IL-18 polypeptide comprises T63A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue Q103. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises Q103R substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises Q103E substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises Q103K substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue G108. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises G108A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue H109. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises H109A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue D110. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises D110A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue D132. In certain embodiments, the IL- 18 polypeptide of the Act-IL-18 polypeptide comprises D132A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue V153. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises V153R substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises V153E substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises V153Y substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue C38. In certain -129- 49194109.1 ES Docket No.94917-0155.737601WO embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C38A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C38S substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue C68. In certain embodiments, the IL-18 polypeptide of the Act- IL-18 polypeptide comprises C68A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C68S substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue C76. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C76A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C76S substitution. In certain embodiments, the modified IL-18 polypeptide comprises a substitution at residue C127. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C127A substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C127S substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a substitution at residue C38, C68, C76, and / or C127. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises a C38A, C38S, C68A, C68S, C76A, C76S, C127A, and / or C127S substitution. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C38A, C76A, and C127A substitutions. In certain embodiments, the IL-18 polypeptide of the Act-IL-18 polypeptide comprises C38S, C76S and C127S substitutions. In some embodiments, the modified IL-18 polypeptide comprises at least one additional modification to the amino acid sequence of SEQ ID NO: 1 selected from: Y01X, F02X, E06X, S10X, V11X, D17X, C38X, M51X, K53X, D54X, S55X, T63X, C68X, E69X, K70X, C76X, E85X, M86X, T95X, D98X, AND C127X, wherein each X is independently a natural or non- natural amino acid. In some embodiments, the modified IL-18 polypeptide comprises at least one additional modification to the amino acid sequence of SEQ ID NO: 1 selected from: Y01G, F02A, E06K, S10T, V11I, D17N, C38S, C38A, C38Q, M51G, K53A, D54A, S55A, T63A, C68S, C68A, E69C, K70C, C76S, C76A, E85C, M86C, T95C, D98C, C127A, and C127S. In some embodiments, the Act-IL-18 polypeptide of an activatable immunocytokine comprises a modified IL-18 polypeptide comprising E06K and K53A, wherein residue position numbering of the modified IL-18 polypeptide is based on SEQ ID NO: 1 as a reference sequence. In some embodiments, the modified IL-18 polypeptide further comprises T63A. In some -130- 49194109.1 ES Docket No.94917-0155.737601WO embodiments, the modified IL-18 polypeptide further comprises at least one of Y01X, S55X, F02X, D54X, C38X, C68X, E69X, K70X, C76X, or C127X, wherein each X is independently an amino acid or an amino acid derivative. In some embodiments, the modified IL-18 polypeptide further comprises at least one of Y01G, S55A, F02A, D54A, C38S, C38A, C68S, C68A, K70C, C76S, C76A, C127S, or C127A. In some embodiments, the modified IL-18 peptide comprises at least one modification to the amino acid sequence of SEQ ID NO: 1, wherein the modification is E06X, K53X, S55X, or T63X, wherein X is a natural or non-natural amino acid. In some embodiments, the modified IL- 18 peptide comprises at least two additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise E06X and K53X; E06X and S55X; K53X and S55X; E06X and T63X; or K53X and T63X, wherein X is a natural or non-natural amino acid. In some embodiments, the modified IL-18 peptide comprises at least three additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise E06X, K53X, and S55X; or E06X, K53X, and T63X, wherein X is a natural or non-natural amino acid. In some embodiments, the modified IL-18 peptide comprises at least four additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise E06X, K53X, S55X, and T63X; E06X, K53X, S55X, and Y01X; E06X, K53X, S55X, and F02X; E06X, K53X, S55X, and D54X; E06X, K53X, S55X, and M51X; or C38X, C68X, C76X, and C127X, wherein X is a natural or non-natural amino acid. In each embodiment wherein a plurality of amino acids residues are replaced with a natural or non-natural amino acid X, each X is independently the same or a different amino acid. In some embodiments, the modified IL-18 peptide comprises at least one additional modification to the amino acid sequence of SEQ ID NO: 1, wherein the modification is E06K, V11I, K53A, S55A, or T63A. In some embodiments, the modified IL-18 peptide comprises at least two additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise E06K and K53A; E06K and S55A; K53A and S55A; E06K and T63A; or K53A and T63A. In some embodiments, the modified IL-18 peptide comprises at least three additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise E06K, K53A, and S55A; E06K, V11I, and K53A; E06K, C38A, and K53A; or E06K, K53A, and T63A. In some embodiments, the modified IL-18 peptide comprises at least four additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications -131- 49194109.1 ES Docket No.94917-0155.737601WO comprise E06K, K53A, S55A, and T63A; E06K, K53A, S55A, and Y01G; E06K, K53A, S55A, and F02A; E06K, K53A, S55A, and D54A; E06K, K53A, S55A, and M51G; or C38S, C68S, C76S, and C127S. In some embodiments, the modified IL-18 peptide comprises at least six modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise E06K, K53A, C38S, C68S, C76S, and C127S; or K53A, T63A, C38S, C68S, C76S, and C127S. In some embodiments, the modified IL-18 polypeptide comprises at least seven modifications to the sequence of SEQ ID NO: 1, wherein the seven modifications comprise E6K, V11I, C38A, K53A, T63A, C76A, C127A. In some embodiments, the modified IL-18 peptide comprises at least eight modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise Y01G, F02A, E06K, M51G, K53A, D54A, S55A, and T63A. In some embodiments, the modified IL-18 peptide comprises at least eight additional modifications to the amino acid sequence of SEQ ID NO: 1, wherein the modifications comprise Y01G, F02A, E06K, M51G, K53A, D54A, S55A, and T63A. In one aspect, provided herein, is a modified IL-18 polypeptide with a polymer as provided herein (e.g., a polymer attached to a residue as provided herein), further comprising E06K and K53A, wherein residue position numbering of the modified IL-18 polypeptide is based on SEQ ID NO: 1 as a reference sequence. In some embodiments, the modified IL-18 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the modified IL- 18 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the modified IL-18 polypeptide further comprises an amino acid substitution at one or more cysteine residues. In some embodiments, the modified IL-18 polypeptide comprises one or more cysteines substituted with either serine or alanine. In some embodiments, the modified IL- 18 polypeptide comprise amino acid substitutions at each cysteine residue of SEQ ID NO: 1. In some embodiments, each cysteine residue is substituted with serine or alanine. In some embodiments, the modified IL-18 polypeptide comprises a polymer covalently attached to an amino acid residue. In some embodiments, the modified IL-18 polypeptide comprises amino acid substitutions at 1, 2, 3, 4, 5, or 6 methionine residues. An IL-18 polypeptide of an Act-IL-18 polypeptide as described herein can comprise one or more non-canonical amino acids. “Non-canonical” amino acids can refer to amino acid residues -132- 49194109.1 ES Docket No.94917-0155.737601WO in D- or L-form that are not among the 20 canonical amino acids generally incorporated into naturally occurring proteins. In some embodiments, one or more amino acids of the active form of the Act-IL-18 polypeptides are substituted with one or more non-canonical amino acids. Non- canonical amino acids include, but are not limited to N-alpha-(9-Fluorenylmethyloxycarbonyl)-L- azidolysine (Fmoc-L-Lys(N3)-OH), N-alpha-(9-Fluorenylmethyloxycarbonyl)-L-biphenylalanine (Fmoc-L-Bip-OH), and N-alpha-(9-Fluorenylmethyloxycarbonyl)-O-benzyl-L-tyrosine (Fmoc-L- Tyr(Bzl)-OH. Exemplary non-canonical amino acids include azido-lysine (AzK), hydroxylysine, allo- hydroxylysine, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, 5-hydroxylysine, Fmoc-Lys (Me, Boc), Fmoc-Lys (Me)3, Fmoc-Lys (palmitoyl), Fmoc-L-photo-lysine, DL-5-hydroxylysine, H-L- photo-lysine, and / or other similar amino acids. Example non-canonical amino acids also include D-methionine, selenocysteine, and / or other similar amino acids. Exemplary non-canonical amino acids also include p-acetyl-L-phenylalanine, p-iodo-L- phenylalanine, p-methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p- propargyl-phenylalanine, L-3-(2-naphthyl) alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl- L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-Boronophenylalanine, O-propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L- phenylalanine, an analogue of a tyrosine amino acid; an analogue of a glutamine amino acid; an analogue of a phenylalanine amino acid; an analogue of a serine amino acid; an analogue of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynyl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid, a β-amino acid; a cyclic amino acid other than proline or histidine; an aromatic amino acid other than phenylalanine, tyrosine or tryptophan; or a combination thereof. In some embodiments, the non-canonical amino acids are selected from β-amino acids, homoamino acids, cyclic amino acids and amino acids with derivatized side chains. In some embodiments, the non-canonical amino acids comprise β-alanine, β-aminopropionic acid, piperidinic acid, aminocaprioic acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid, Nα-ethylglycine, Nα-ethylaspargine, isodesmosine, allo-isoleucine, ω- -133- 49194109.1 ES Docket No.94917-0155.737601WO methylarginine, Nα-methylglycine, Nα-methylisoleucine, Nα-methylvaline, γ-carboxyglutamate, O-phosphoserine, Nα-acetylserine, Nα-formylmethionine, 3-methylhistidine, and / or other similar amino acids. In some embodiments, amino acid residues of the Act-IL-18 polypeptides are substituted with modified lysine residues. In some embodiments, the modified lysine residues comprise an the 18 a ES Docket No.94917-0155.737601WO O ON3OON NH n H H , n the a 18 of reacting with a complementary reactive group. In some embodiments, the conjugation handle comprises a reagent for a Cu(I)-catalyzed or "copper-free" alkyne-azide triazole-forming reaction (e.g., strain promoted cycloadditions), the Staudinger ligation, inverse-electron-demand Diels- Alder (IEDDA) reaction, "photo-click" chemistry, tetrazine cycloadditions with trans-cycloctenes, potassium acyl trifluoroborate (KAT) ligations, or a metal-mediated process such as olefin metathesis and Suzuki- Miyaura or Sonogashira cross-coupling. In some embodiments, the conjugation handle comprises a reagent for a “copper-free” alkyne azide triazole-forming reaction. Non-limiting examples of alkynes for said alkyne azide triazole forming reaction include cyclooctyne reagents (e.g., (1R,8S,9s)-Bicyclo[6.1.0]non-4-yn- -135- 49194109.1 ES Docket No.94917-0155.737601WO 9-ylmethanol containing reagents, dibenzocyclooctyne-amine reagents, difluorocyclooctynes, or derivatives thereof). In some embodiments, the conjugation handle comprises a reactive group selected from azide, alkyne, tetrazine, halide, sulfhydryl, disulfide, maleimide, activated ester, alkene, aldehyde, ketone, imine, hydrazine, acyltrifluoroborate, hydroxylamine, phosphine, trans-cyclooctene, and hydrazide. In some embodiments, the conjugation handle and complementary conjugation handle comprise “CLICK” chemistry reagents. Exemplary groups of click chemistry residue are shown in Hein et al., “Click Chemistry, A Powerful Tool for Pharmaceutical Sciences,” Pharmaceutical Research, volume 25, pages 2216–2230 (2008); Thirumurugan et al., “Click Chemistry for Drug Development and Diverse Chemical–Biology Applications,” Chem. Rev. 2013, 113, 7, 4905– 4979; US20160107999A1; US10266502B2; and US20190204330A1, each of which is incorporated by reference in its entirety. In some embodiments, a group attached to the Act-IL-18 polypeptide (e.g., a polymer moiety or an additional polypeptide) comprises a conjugation handle or a reaction product of a conjugation handle with a complementary conjugation handle. In some embodiments, the reaction product of the conjugation handle with the complementary conjugation handle results from a KAT ligation (reaction of potassium acyltrifluoroborate with hydroxylamine), a Staudinger ligation (reaction of an azide with a phosphine), a tetrazine cycloaddition (reaction of a tetrazine with a trans-cyclooctene), or a Huisgen cycloaddition (reaction of an alkyne with an azide). In some embodiments, the group attached to the IL-18 polypeptide (e.g., the polymer or the additional polypeptide) will comprise a reaction product of a conjugation handle with a complementary conjugation handle which was used to attach the group to the Act-IL-18 polypeptide. The Active form of the IL-18 Polypeptide In some embodiments, cleavage of the protease cleavage site of the artificial polypeptide converts the Act-IL-18 into an active form of the IL-18 polypeptide, which preferably remains attached to the antibody or antigen binding fragment after cleavage. As used herein, the active form of the IL-18 polypeptide refers to the cleaved version of the IL-18 polypeptide which possesses some or all of the activity associated with the IL-18 polypeptide which is inactivated by the artificial polypeptide. Additionally, unless context clearly indicates otherwise, reference to simply “the IL-18 polypeptide” refers to an IL-18 polypeptide which was never prepared in an activatable form (E.g., it refers to the base IL-18 polypeptide on which an Act-IL-18 polypeptide -136- 49194109.1 ES Docket No.94917-0155.737601WO is based). In some embodiments, the active form of the IL-18 polypeptide comprises a portion the artificial polypeptide still attached to the IL-18 polypeptide (e.g., a subset of amino acid residues of the artificial polypeptide). In some embodiments, the active form of the IL-18 polypeptide is the same as the IL-18 polypeptide (e.g., has the same amino acid sequence as the IL-18 polypeptide because the entire artificial polypeptide has been cleaved). It is expected that activities associated with the IL-18 polypeptide (activated or non-activated form) will be substantially the same when the molecule is attached to the antibody or antigen binding fragment. For any of the activities described below, it is similarly contemplated herein that such activities can also apply to an activated immunocytokine provided herein (i.e., for each of the activities described below, the activities can also refer to the activity of the activated immunocytokine instead of the free activated IL-18 polypeptide). In some embodiments, the active form of the IL-18 polypeptide provided herein display reduced binding to the IL-18 binding protein (IL-18BP) relative to WT-IL-18. The active form of the IL-18 polypeptides may also display binding characteristics for the IL-18Rab that differ from wild-type IL-18 (e.g., a higher affinity for the IL-18Rab heterodimer or a lower affinity for the IL- 18Rab heterodimer). In preferred embodiments, the affinity for IL-18Rab of the active form of the IL-18 polypeptide is not substantially lower than the affinity of WT IL-18 for IL-18Rab (e.g., the active form of the Act-IL-18 polypeptide’s affinity for IL-18Rab is no less than about 500x lower than wild type IL-18). In some embodiments, the active form of the IL-18 polypeptides displays increased affinity for an IL-18 receptor alpha subunit (IL-18Ra) or an IL-18 receptor beta subunit (IL-18Rb) relative to wild type IL-18. In some embodiments, the active form of the IL-18 polypeptides have an increased affinity for the IL-18Ra / b heterodimer relative to IL-18 WT. In one aspect, the active form of the IL-18 polypeptides described herein have decreased affinity for the IL-18Ra / b heterodimer relative to wild type IL-18. In some embodiments, the binding affinity between the active form of the IL-18 polypeptides and IL-18Ra is the same as or lower than the binding affinity between a wild-type IL-18 and IL-18Ra. In some embodiments, the binding affinity between the active form of the IL- 18 polypeptides and IL-18Ra is the same as or higher than the binding affinity between a wild- type IL-18 and IL-18Ra. In some embodiments, the binding affinity between the active form of the IL-18 polypeptides and IL-18Rb is the same as or lower than the binding affinity between a -137- 49194109.1 ES Docket No.94917-0155.737601WO wild-type IL-18 and IL-18Rb. In some embodiments, the binding affinity between the active form of the IL-18 polypeptides and IL-18Rb is the same as or higher than the binding affinity between a wild-type IL-18 and IL-18Rb. In some embodiments, the binding affinity between the active form of the IL-18 polypeptides and the IL-18Rα / b heterodimer is the same as or lower than the binding affinity between a wild-type IL-18 and the IL-18Rα / b heterodimer. In some embodiments, the binding affinity between the active form of the IL-18 polypeptides and the IL-18Rα / b heterodimer is the same as or higher than the binding affinity between a wild-type IL-18 and the IL-18Rα / b heterodimer. In some embodiments, an active form of the IL-18 polypeptide provided herein displays an ability to induce interferon gamma (IFNγ) production after administration to a subject. In some of 18 a -138- 49194109.1 ES Docket No.94917-0155.737601WO Points of Attachment of Chemical Linkers to IL-18 Polypeptides The activatable immunocytokines provided herein comprise linkers which have a point of attachment to the Act-IL-18 polypeptide. In some embodiments, the linker is a chemical linker. As discussed supra, the linker has another point of attachment to the antibody or antigen binding fragment at any residue as provided herein. The point of attachment to the Act-IL-18 polypeptide is to a residue as provided herein. In some preferred embodiments, the linker is attached to the IL- 18 polypeptide such that the IL-18 polypeptide remains tethered to the antibody or antigen binding fragment after cleavage of the artificial polypeptide attached (i.e., the active form of the IL-18 polypeptide remains attached to the antibody or antigen binding fragment thereof). In some embodiments, the linker is attached to an amino acid residue of the IL-18 polypeptide of the Act-IL-18 polypeptide. In some embodiments, the linker is attached to any amino acid residue of the IL-18 polypeptide (e.g., at a position corresponding to any one of positions 1-157 of SEQ ID NO: 1). In some embodiments, the linker is attached at a non-terminal residue of the IL-18 polypeptide (e.g., a residue at position corresponding to any one of positions 2-156 of SEQ ID NO: 1). In some embodiments, the linker is attached at a non-terminal residue of the Act-IL-18 polypeptide, wherein the IL-18 polypeptide has been extended or truncated by one or more amino acids relative to SEQ ID NO: 1. In some embodiments, the linker is attached to the IL-18 polypeptide of the Act-IL-18 polypeptide at a residue in a region comprising residues 2-156, wherein residue position numbering is based on SEQ ID NO: 1 as a reference sequence. In some embodiments, the linker is attached to the IL-18 polypeptide at a residue in a region comprising residues 30-150. In some embodiments, the linker is attached to the IL-18 polypeptide at a residue in a region comprising residues 33-43, residues 60-100, residues 65-75, residues 80-90, residues 85-100, residues 90-110, residues 115-130, residues 120-130, or residues 140-150. In some embodiments, the linker is attached to the IL-18 polypeptide at a residue selected from residue 38, 68, 69, 70, 76, 78, 85, 86, 95, 98, 121, 127, and 144. In some embodiments, the linker is attached to the IL-18 polypeptide at a residue selected from 68, 69, 70, 85, 86, and 98. In some embodiments, the linker is attached to the IL-18 polypeptide at residue 68, 69, or 70. In some embodiments, the linker is attached to the IL-18 polypeptide at residue 85, 86, 95, or 98. In some embodiments, the linker is attached to the IL-18 polypeptide at residue 68. In some embodiments, the linker is attached to the IL-18 polypeptide at residue 69. In some embodiments, the linker is attached to the IL-18 polypeptide at -139- 49194109.1 ES Docket No.94917-0155.737601WO residue 70. In some embodiments, the linker is attached to the IL-18 polypeptide at residue 85. In some embodiments, the linker is attached to the IL-18 polypeptide at residue 86. In some 18 18 on is a the 1. is a In In ES Docket No.94917-0155.737601WO some embodiments, the linker is covalently attached site-specifically to the unnatural amino acid. Non-limiting examples of amino acid residues comprising conjugation handles can be found, for example, in PCT Pub. Nos. WO2015054658A1, WO2014036492A1, WO2021133839A1 WO2006069246A2, and WO2007079130A2, each of which is incorporated by reference as if set forth in its entirety. In some embodiments, the linker is covalently attached at residue 68. In some embodiments, the linker is covalently attached at residue C68, C68E, C68D, C68Q, C68K, C68N, or C68Y. In some embodiments, the linker is covalently attached at residue C68. In some embodiments, the linker is covalently attached to an unnatural amino acid at residue 68. In some embodiments, the linker is covalently attached at residue 69. In some embodiments, the linker is covalently attached at residue E69, E69C, E69D, E69Q, E69K, E69N, or E69Y. In some embodiments, the linker is covalently attached at residue E69. In some embodiments, the linker is covalently attached residue E69C. In some embodiments, the linker is covalently attached to an unnatural amino acid at residue 69. In some embodiments, the linker is covalently attached at residue 70. In some embodiments, the linker is covalently attached at residue K70, K70C, K70D, K70Q, K70E, K70N, or K70Y. In some embodiments, the linker is covalently attached at residue K70. In some embodiments, the linker is covalently attached residue K70C. In some embodiments, the linker is covalently attached to an unnatural amino acid at residue 70. In some embodiments, the linker is covalently attached at residue 85. In some embodiments, the linker is covalently attached at residue E85, E85C, E85D, E85Q, E85K, E85N, or E85Y. In some embodiments, the linker is covalently attached at residue E85. In some embodiments, the linker is covalently attached residue E85C. In some embodiments, the linker is covalently attached to an unnatural amino acid at residue 85. In some embodiments, the linker is covalently attached at residue 86. In some embodiments, the linker is covalently attached at residue M86C, M86D, M86Q, M86K, M86N, M86E, or M86Y. In some embodiments, the linker is covalently attached M86C. In some embodiments, the linker is covalently attached to an unnatural amino acid at residue 86. In some embodiments, the polymer is covalently attached at residue 95. In some embodiments, the polymer is covalently attached at residue T95, T95C, T95D, T95Q, T95K, T95N, T95E, or T95Y. In some embodiments, the polymer is covalently attached at residue T95C, -141- 49194109.1 ES Docket No.94917-0155.737601WO T95D, T95Q, T95K, T95N, T95E, or T95Y. In some embodiments, the polymer is covalently attached at residue T95C. In some embodiments, the polymer is covalently attached to an unnatural amino acid at residue 95. In some embodiments, the linker is covalently attached at residue 98. In some embodiments, the linker is covalently attached at residue D98, D98C, D98Q, D98K, D98N, D98E, or D98Y. In some embodiments, the linker is covalently attached at residue D98C. In some embodiments, the linker is covalently attached to an unnatural amino acid at residue 98. In some embodiments, the linker is covalently attached through a modified natural amino acid. In some embodiments, the modified natural amino acid comprises a conjugation handle. In some embodiments, the linker is covalently attached through a modified amino acid α. In some embodiments, the modified amino acid α is an amino-acid-PEG-azide group. In some embodiments, the modified amino acid α is a glutamate, aspartate, lysine, cysteine, or tyrosine modified to incorporate an azide group linked to the amino acid through a PEG spacer. In some embodiments, the modified amino acid α has a structure selected from: O O N3OON NH H 8, of the IL-18 polypeptide of an Act-IL-18 polypeptide as provided herein. In some embodiments, -142- 49194109.1 ES Docket No.94917-0155.737601WO the modified amino acid α is located at a position on the modified IL-18 polypeptide selected from residue 68, residue 69, residue 70, residue 85, residue 86, residue 95, or residue 98. Where IL-18 polypeptides of Act-IL-18 polypeptides contain unnatural amino acids or modified natural amino acids (e.g., those provided herein for purposes of conjugation), these amino acids may be incorporated into the IL-18 polypeptides using many techniques known in the art for introduction such modifications. For example, recombinant proteins with unnatural amino acids can be made using methods as described in Patent Cooperation Treaty Publication Nos. WO2016115168, WO2002085923, WO2005019415, and WO2005003294. Alternatively, or in combination, unnatural or modified natural amino acids can be incorporated into chemically synthesized proteins during synthesis. In some embodiments, the linker is attached to the C-terminus of the IL-18 polypeptide, optionally by a linking peptide (e.g., any one of the linking peptides described herein). In some embodiments, the linker is attached using a sortase mediated reaction. For example, an IL-18 polypeptide described herein can have a sortase recognition sequence (e.g., LPETGGH) appended to the C-terminus of the IL-18 polypeptide, optionally via a linking peptide, such as those described herein. The IL-18 polypeptide (e.g., as incorporated into an Act-IL-18 polypeptide) can then be reacted with a suitable donor group (e.g., an additional group containing an N-terminal glycine, preferably a polyglycine). The donor group can be a polypeptide (e.g., a full length protein desired to be attached to the Act-IL-18 polypeptide, such as an antibody as described herien to directly form an activatable immunocytokine), or can be a small peptide comprising a conjugation handle (e.g., a short peptide of, e.g., 2-10 amino acids, which comprises at least 1, preferably 2-3 N- terminal glycine residue(s) linked to a suitable conjugation handle). Exemplary linkers which can be attached via sortase include the GGK-PEG9-N3 and GGE-PEG9-N3 reagents shown below, though other similar such linkers can also be added (e.g., ones which have variable PEG sizes, alternative amino acids attached to the GG group, alternative conjugation handles, etc.). As is apparent to one of ordinary skill in the art, in the sortase region, the “GGH” portion of the sortase recognition sequence is replaced by the glycine (or polyglycine) containing sequence of the reagent (or additional group polypeptide as the case may be). Descriptions of sortase mediated conjugation to proteins can be found in, for example, Patent Cooperation Treaty Publication Nos. WO2013 / 003555A1, WO2014 / 140317A2, and WO2020 / 007899A1. -143- 49194109.1 ES Docket No.94917-0155.737601WO GGK-PEG9-N3 H N O NH O In some embodiments the Act-IL-18 (either free or incorporated into an activatable immunocytokine) exhibits a decreased affinity for the IL-18 receptor of at least 10-fold, at least an at at for ES Docket No.94917-0155.737601WO exhibits at least a 20-fold lower affinity for IL-18BP compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide exhibits at least a 50-fold lower affinity for IL-18BP compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide exhibits at least an 80-fold lower affinity for IL-18BP compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide exhibits at least a 100-fold lower affinity for IL-18BP compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide provided herein (either free or incorporated into an activatable immunocytokine) exhibits a reduced binding to IL-18BP as measured by KD. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18BP of at least about 1 nM, at least about 5 nM, at least about 10 nM, at least about 15 nM, at least about 20 nM, at least about 25 nM, at least about 50 nM, at least about 100 nM, at least about 200 nM, at least about 300 nM, at least about 400 nM, or at least about 500 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18BP of at least about 1 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18BP of at least about 5 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18BP of at least about 50 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18BP of at least about 100 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18BP of at least about 500 nM. In some embodiments, the active form of the IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) displays at most an only slightly diminished affinity for IL- 18Rab compared to WT IL-18 (SEQ ID NO: 1). In some embodiments, the active form of the IL- 18 polypeptide exhibits at most a 2-fold lower, at most a 3-fold lower, at most a 4-fold lower, at most 5-fold lower, at most a 10-fold lower, at most a 15-fold lower, at most a 20-fold lower, at most a 30-fold lower, at most a 40-fold lower, at most a 50-fold lower, at most a 75-fold lower, or at most a 100-fold lower affinity for IL-18 Rab as compared to the affinity of WT IL-18 for IL- 18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 10-fold lower affinity for IL-18Rab as compared to the affinity of WT IL-18 for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 20-fold lower affinity for IL-18Rab as compared to the affinity of WT IL-18 for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 50-fold lower affinity for IL-18Rab as -145- 49194109.1 ES Docket No.94917-0155.737601WO compared to the affinity of WT IL-18 for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 100-fold lower affinity for IL-18 Rab as compared to the affinity of WT IL-18 for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits an increased affinity for IL-18Rab compared to WT IL-18. In some embodiments, the affinity is increased by at least 2-fold, at least 4-fold, at least 6-fold, at least 8-fold, or at least 10- fold compared to WT IL-18. In some embodiments, the active form of the IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) displays at most an only slightly diminished affinity for IL- 18Rab compared to the corresponding IL-18 polypeptide without the artificial polypeptide. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 2-fold lower, at most a 3-fold lower, at most a 4-fold lower, at most 5-fold lower, at most a 10-fold lower, at most a 15-fold lower, at most a 20-fold lower, at most a 30-fold lower, at most a 40-fold lower, at most a 50-fold lower, at most a 75-fold lower, or at most a 100-fold lower affinity for IL-18 Rab as compared to the affinity of the corresponding IL-18 polypeptide without the artificial polypeptide for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 2-fold lower affinity for IL-18Rab as compared to the affinity of the corresponding IL-18 polypeptide without the artificial polypeptide for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 3-fold lower affinity for IL-18Rab as compared to the affinity of the corresponding IL-18 polypeptide without the artificial polypeptide for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 4-fold lower affinity for IL-18Rab as compared to the affinity of the corresponding wild type IL-18 polypeptide without the N-terminal domain for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 5-fold lower affinity for IL-18 Rab as compared to the affinity of the corresponding IL-18 polypeptide without the artificial polypeptide for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide exhibits at most a 10-fold lower affinity for IL-18Rab as compared to the affinity of the corresponding IL-18 polypeptide without the artificial polypeptide for IL-18Rab. In some embodiments, the active form of the IL-18 polypeptide provided herein (either free or incorporated into an activatable immunocytokine) exhibits at most only a slight reduction in binding to IL-18Rab as measured by KD. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18Rab of at most about 10 nM, at most about 20 nM, at most -146- 49194109.1 ES Docket No.94917-0155.737601WO about 30 nM, at most about 50 nM, at most about 75 nM, at most about 100 nM, or at most about 200 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL- 18Rab of at most about 20 nM. In some embodiments, the active form of the Act-IL-18 polypeptide exhibits a KD with IL-18Rab of at most about 30 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18Rab of at most about 40 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits a KD with IL-18Rab of at most about 50 nM. In some embodiments, the active form of the IL-18 polypeptide exhibits an increase in binding to IL- 18Rab compared to WT IL-18 as measured by KD. In some embodiments, the active form of the IL-18 polypeptide has a KD with IL-18Ra of at most about 2 nM, at most about 1 nM, at most about 0.5 nM, or at most about 0.2 nM. In some embodiments, the active form of the IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) exhibits a wide window in which the active form of the IL- 18 polypeptide will bind to IL-18Rab even in the presence of IL-18BP. In some embodiments, this window can be measured by a ratio of KD of the Act-IL-18 / IL-18BP interaction over KD of the IL-18 / IL-18Rab interaction, where a larger number indicates a larger window in which the active form of the Act-IL-18 polypeptide is expected to be active in vivo. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL-18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, or at least about 50. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 2. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 5. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 10. . In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 25. .In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 30. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- -147- 49194109.1 ES Docket No.94917-0155.737601WO 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 40. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 45. In some embodiments, the active form of the IL-18 polypeptide exhibits a ratio of KD of the IL-18 / IL- 18BP interaction over KD of the IL-18 / IL-18Rab interaction of at least about 50. Functional Activity of the activated form of the IL-18 Polypeptide In some embodiments, the active form of the IL-18 polypeptides provided herein (either free or incorporated into an activatable immunocytokine) display one or more activities associated with WT IL-18. In some embodiments, the active form of the IL-18 polypeptide exhibits a similar ability to signal through the IL-18 receptor (IL-18Rab) but lacks the ability or displays a reduced ability to be inhibited by IL-18BP. In some embodiments, the active form of the IL-18 polypeptide’s ability to signal through IL-18Rab is reduced compared to WT IL-18 by only a small amount. In some embodiments, the active form of the IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) modulates IFNγ production when in contact with a cell (e.g., 18 18 18 18 ES Docket No.94917-0155.737601WO In some embodiments, an EC50 of the active form of the IL-18 polypeptide’s ability to induce IFNγ production (either free or incorporated into an activatable immunocytokine) is less 18 of a at ES Docket No.94917-0155.737601WO about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, at least about 600-fold, at least about 700-fold, at least about 800-fold, at least about 900-fold, or at least about 1000-fold compared to WT IL-18. In some embodiments, the IC50 / EC50 ratio is increased by at least about 10-fold compared to WT IL-18. In some embodiments, the IC50 / EC50 ratio is increased by at least about 100-fold compared to WT IL-18. In some embodiments, the IC50 / EC50 ratio is increased by at least about 500-fold compared to WT IL-18. In some embodiments, the IC50 / EC50 ratio of the active form of the Act-IL-18 polypeptide is at least about 2, at least about 5, at least about 10, at least about 50, at least about 100, at least about 250, or at least about 500. In some embodiments, the active form of the IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) modulates IFNγ production, and wherein an EC50 (nM) of the active form of the Act-IL-18 polypeptide against IFNγ is less than an EC50 (nM) of an IL-18 polypeptide of SEQ ID NO: 1. In some embodiments, the EC50 (nM) of the active form of the Act-IL-18 polypeptide against IFNγ is at least 10-fold less than the EC50 (nM) of an IL-18 polypeptide of SEQ ID NO: 1. In some embodiments, the EC50 (nM) of the active form of the Act-IL-18 polypeptide against IFNγ is about 10-fold less than the EC50 (nM) of an IL-18 polypeptide of SEQ ID NO: 1. In some embodiments, the EC50 (nM) of the active form of the Act-IL-18 polypeptide against IFNγ is about 15-fold less than the EC50 (nM) of a n IL-18 polypeptide of SEQ ID NO: 1. Relative Activity of the Activatable and Active form of IL-18 In some embodiments, the activated form of the IL-18 polypeptide (e.g., after cleavage of the specific cleavage site) (either free or incorporated into an activatable immunocytokine) exhibits an enhanced activity associated with IL-18 compared to the Act-IL-18 polypeptide with the specific cleavage site intact. In some embodiments, the active form of the IL-18 polypeptide exhibits an activity which is enhanced by at least 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200- fold, 500-fold, 1000-fold, 2000-fold, 5000-fold, 10000-fold, 15000-fold, or 20,000-fold higher than the Act-IL-18 polypeptide. Such activities can include induction of production of IFNγ in a cell (e.g., an immune cell such as an NK cell), activation of signaling through the IL-18 receptor (e.g., in a reporter assay), or another in vitro or in vivo activity. In some embodiments, the activated form of the IL-18 polypeptide exhibits enhanced binding to the IL-18 receptor or a subunit thereof (e.g., the IL-18 receptor alpha subunit) compared to the Act-IL-18 polypeptide (e.g., has a KD which is at least 10-fold, 20-fold, 50-fold, or 100-fold lower). -150- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the Act IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) exhibits a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity (e.g., in a HEK-Blue reporter assay) which is higher than that of the activated form of the IL-18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits an EC50 for IL-18 receptor signaling activity which is at least 1,000-fold higher, 2,000-fold higher, 5,000-fold higher, 10,000-fold higher, 15,000-fold-higher, or 20,000-fold higher than the activated form of the IL-18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits an EC50 for IL-18 receptor signaling activity which is at least 1,000-fold higher than the activated form of the IL-18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits an EC50 for IL- 18 receptor signaling activity which is at least 5,000-fold higher than the activated form of the IL- 18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits an EC50 for IL-18 receptor signaling activity which is at least 10,000-fold higher than the activated form of the IL- 18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits an EC50 for IL-18 receptor signaling activity which is at least 20,000-fold higher than the activated form of the IL- 18 polypeptide. In some embodiments, the Act-IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) exhibits only a modest reduction in activity compared to the activated form of the IL-18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is from about 10-fold higher to about 100-fold higher than the activated form of the IL-18 polypeptide. In some embodiments, the Act IL-18 polypeptide exhibits an EC50 for IL-18 receptor signaling activity which is from about 10-fold higher to about 50-fold higher than the activated form of the IL-18 polypeptide. In some embodiments, the activated form of the IL-18 polypeptide (either free or incorporated into an activatable immunocytokine) has a comparable activity compared to that of the IL-18 polypeptide from which the Act-IL-18 polypeptide is derived. In some embodiments, the activated form of the IL-18 polypeptide exhibits a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is within about 10-fold of the IL-18 polypeptide. Biological Activity of the Immunocytokines. -151- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, an immunocytokine described herein exhibits one or more activities associated with the antibody or antigen binding fragment and / or an IL-18 polypeptide after cleavage of the Act-IL-18. In some embodiments, the immunocytokine exhibits an ability to bind to the IL-18 receptor. In some embodiments, the immunocytokine exhibits an ability to bind to the IL-18 receptor after cleavage of the Act-IL-18 which is comparable to WT IL-18. In some embodiments, immunocytokine exhibits an ability to bind to the IL-18 receptor (IL-18Rαβ) which is reduced by at most 2-fold, at most 5-fold, at most 10-fold, at most 20-fold, at most 50-fold, at most 100-fold, at most 200-fold, at most 300-fold, at most 400-fold, or at most 1000-fold compared to WT IL-18. In some embodiments, the immunocytokine exhibits an enhanced ability to bind the IL-18Rαβ. In some embodiments, the immunocytokine exhibits an ability to bind to the IL-18Rαβ which is increased by at least 2-fold, at least 3-fold, at least 5-fold, or at least 10-fold compared to WT IL- 18. In some embodiments, the immunocytokine exhibits an ability to stimulate production of IFNγ upon contact with a cell (e.g., an immune cell, such as an NK cell) after cleavage of the Act- IL-18. In some embodiments, the ability of the immunocytokine to stimulate IFNγ production is somewhat reduced compared to WT IL-18. In some embodiments, a half-maximal effective concentration (EC50) of the ability of the immunocytokine to stimulate production of IFNγ is at most 100-fold higher than, at most 50-fold higher than, at most 20-fold higher than, at most 10- fold higher than, at most 5-fold higher than, or at most 2-fold higher than that of a WT IL-18. In some embodiments, the ability of the immunocytokine to stimulate IFNγ production is enhanced compared to WT IL-18. In some embodiments, a half-maximal effective concentration (EC50) of the ability of the immunocytokine to stimulate production of IFNγ is at least 5-fold lower than, at least 10-fold lower than, at least 20-fold lower than, at least 50-fold lower than, at least 75-fold lower than, or at least 100-fold higher than that of a WT IL-18. In some embodiments, the immunocytokine exhibits an ability to stimulate production of IFNγ upon contact with a cell (e.g., an immune cell, such as an NK cell) after cleavage of the Act- IL-18 which is only somewhat reduced as compared to the IL-18 polypeptide not comprised in the immunocytokine (e.g., unconjugated IL-18 polypeptide). In some embodiments, the EC50 of IFNγ stimulation is at most 5-fold greater than, at most 10-fold greater than, at most 50-fold greater than, -152- 49194109.1 ES Docket No.94917-0155.737601WO or at most 100-fold greater than that that of the IL-18 polypeptide not comprised in the immunocytokine. In some embodiments, the immunocytokine exhibits an ability to induce IFNγ production in a cell as measured by half-maximal effective concentration (EC50) which is within about 100-fold of the corresponding IL-18 polypeptide not comprised in the immunocytokine. In some embodiments, the immunocytokine exhibits a lower EC50than WT IL-18. In some embodiments, the immunocytokine exhibits a lower EC50 than WT IL-18 by at least 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, or 100-fold. In some embodiments, the immunocytokine exhibits a reduced ability to bind IL-18 binding protein (IL-18BP) before and after cleavage of the Act-IL-18. In some embodiments, the ability of immunocytokine to bind IL-18BP is reduced by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, or at least 100-fold compared to WT IL- 18. In some embodiments, the immunocytokine does not display any substantial ability to bind IL- 18 BP. In some embodiments, the immunocytokine exhibits a reduced ability to have its IFNγ production stimulatory activity inhibited by IL-18BP. In some embodiments, the ability of the immunocytokine to be inhibited by IL-18BP is measured as a half maximal inhibitory concentration (IC50). In some embodiments, the immunocytokine exhibits an IC50by IL-18BP that is at least 2-fold higher than, at least 5-fold higher than, at least 10-fold higher than, at least 15- fold higher than, at least 20-fold higher than, at least 25-fold higher than, at least 30-fold higher than, at least 40-fold higher than, or at least 50-fold higher than an IC50 of WT IL-18’s inhibition by IL-18BP. In some embodiments, the immunocytokine exhibits an IC50 by IL-18BP that is at least 100-fold higher than an IC50 of WT IL-18’s inhibition by IL-18BP. In some embodiments, the immunocytokine exhibits an IC50 by IL-18BP that is at least 200-fold higher than an IC50 of WT IL-18’s inhibition by IL-18BP. In some embodiments, the immunocytokine exhibits an IC50 by IL-18BP that is at least 500-fold higher than an IC50 of WT IL-18’s inhibition by IL-18BP. In some embodiments, the immunocytokine exhibits an IC50 by IL-18BP that is at least 1000-fold higher than an IC50 of WT IL-18’s inhibition by IL-18BP. In some embodiments, the immunocytokine retains binding associated with the antibody or antigen binding fragment. In some embodiments, the immunocytokine retains binding to the antigen of the antibody or antigen binding fragment. In some embodiments, the immunocytokine exhibits binding affinity (KD) to the antigen of the antibody which is within 5-fold of the binding -153- 49194109.1 ES Docket No.94917-0155.737601WO affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits binding affinity (KD) to the antigen of the antibody which is within 2.5- fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the binding is determined by ELISA. In some embodiments, the binding is determined by BLI. In some embodiments, the immunocytokine retains binding to one or more Fc receptors associated with the antibody or antigen binding fragment. In some embodiments, the Fc receptor is selected from FcRn, CD64, CD32a, CD16, and CD32b, or any combination thereof. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to at least one Fc receptor which is within 10-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to at least one Fc receptor which is less than 10-fold higher, less than 5-fold higher, less than 4-fold higher, less than 3-fold higher, less than 2-fold higher, or less than the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to each of FcRn, CD64, CD32a, CD16, and CD32B which is less than 10-fold higher, less than 5-fold higher, less than 4-fold higher, less than 3-fold higher, less than 2-fold higher, or less than the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to each of FcRn, CD64, CD32a, CD16, and CD32B which is within 10-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to each of FcRn, CD64, CD32a, CD16, and CD32B which is within 20-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to each of FcRn, CD64, CD32a, CD16, and CD32B which is within 50-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits a binding affinity (KD) to each of FcRn, CD64, CD32a, CD16, and CD32B which is within 100-fold of the binding affinity of the antibody not attached to the IL-18 polypeptide. In some embodiments, the immunocytokine exhibits synergistic efficacy owing to the presence of both molecules in one molecule. In some embodiments, the immunocytokine exhibits enhanced activity compared to either molecule alone. In some embodiments, the immunocytokine exhibits enhanced anti-tumor growth inhibition compared to the antibody alone. In some -154- 49194109.1 ES Docket No.94917-0155.737601WO embodiments, the immunocytokine exhibits enhanced anti-tumor growth inhibition compared to the antibody and the IL-18 polypeptide administered in combination. In some embodiments, the IL-18 polypeptide is administered as a half-life extended version (e.g., PEGylated, attached to an Fc region (e.g., an Fc fusion), or attached to a negative control antibody). In some embodiments, the immunocytokine exhibits similar or enhanced antitumor activity at the same concentration as the antibody administered alone. In some embodiments, the immunocytokine exhibits similar or enhanced antitumor activity when administered at a dose which is less than 0.5-fold, 0.25-fold, or 0.1-fold the dose of the antibody alone. Compositions In one aspect, provided herein is a pharmaceutical composition comprising an antibody linked to a modified IL-18 polypeptide described herein; and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition further comprises one or more excipients, wherein the one or more excipients include, but are not limited to, a carbohydrate, an inorganic salt, an antioxidant, a surfactant, a buffer, or any combination thereof. In some embodiments the pharmaceutical composition further comprises one, two, three, four, five, six, seven, eight, nine, ten, or more excipients, wherein the one or more excipients include, but are not limited to, a carbohydrate, an inorganic salt, an antioxidant, a surfactant, a buffer, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises a carbohydrate. In certain embodiments, the carbohydrate is selected from the group consisting of fructose, maltose, galactose, glucose, D-mannose, sorbose, lactose, sucrose, trehalose, cellobiose raffinose, melezitose, maltodextrins, dextrans, starches, mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, cyclodextrins, and combinations thereof. Alternately, or in addition, the pharmaceutical composition further comprises an inorganic salt. In certain embodiments, the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium sulfate, or combinations thereof. Alternately, or in addition, the pharmaceutical composition further comprises an antioxidant. In certain embodiments, the antioxidant is selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium metabisulfite, -155- 49194109.1 ES Docket No.94917-0155.737601WO propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E, 3,4-dihydroxybenzoic acid, and combinations thereof. Alternately, or in addition, the pharmaceutical composition further comprises a surfactant. In certain embodiments, the surfactant is selected from the group consisting of polysorbates, sorbitan esters, lipids, phospholipids, phosphatidylethanolamines, fatty acids, fatty acid esters, steroids, EDTA, zinc, and combinations thereof. Alternately, or in addition, the pharmaceutical composition further comprises a buffer. In certain embodiments, the buffer is selected from the group consisting of citric acid, sodium phosphate, potassium phosphate, acetic acid, ethanolamine, histidine, amino acids, tartaric acid, succinic acid, fumaric acid, lactic acid, tris, HEPES, or combinations thereof. In some embodiments, the pharmaceutical composition is formulated for parenteral or enteral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous (IV) or subcutaneous (SQ) administration. In some embodiments, the pharmaceutical composition is in a lyophilized form. In one aspect, described herein is a liquid or lyophilized composition that comprises a described antibody or antigen binding fragment linked to a modified IL-18 polypeptide. In some embodiments, the antibody or antigen binding fragment linked to the IL-18 polypeptide modified IL-18 polypeptide is a lyophilized powder. In some embodiments, the lyophilized powder is resuspended in a buffer solution. In some embodiments, the buffer solution comprises a buffer, a sugar, a salt, a surfactant, or any combination thereof. In some embodiments, the buffer solution comprises a phosphate salt. In some embodiments, the phosphate salt is sodium Na2HPO4. In some embodiments, the salt is sodium chloride. In some embodiments, the buffer solution comprises phosphate buffered saline. In some embodiments, the buffer solution comprises mannitol. In some embodiments, the lyophilized powder is suspended in a solution comprising about 10 mM Na2HPO4 buffer, about 0.022% SDS, and about 50 mg / mL mannitol, and having a pH of about 7.5. Dosage Forms The activatable immunocytokines described herein can be in a variety of dosage forms. In some embodiments, the activatable immunocytokine is dosed as a lyophilized powder. In some embodiments, the activatable immunocytokine is dosed as a suspension. In some embodiments, the activatable immunocytokine is dosed as a solution. In some embodiments, the activatable -156- 49194109.1 ES Docket No.94917-0155.737601WO immunocytokine is dosed as an injectable solution. In some embodiments, the activatable immunocytokine is dosed as an IV solution. Methods of Treatment In one aspect, described herein, is a method of treating cancer in a subject in need thereof, comprising: administering to the subject an effective amount of an activatable immunocytokine or 1 an a ES Docket No.94917-0155.737601WO cancer or tumor is reduced by at least 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the activatable immunocytokine is administered in a single dose of the effective amount of activatable immunocytokine, including further embodiments in which (i) the activatable immunocytokine is administered once a day; or (ii) the activatable immunocytokine is administered once a day; or (ii) the activatable immunocytokine is administered to the subject multiple times over the span of one day. In some embodiments, the conjugate is administered daily, every other day, twice a week, 3 times a week, once a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 12 weeks, every 3 days, every 4 days, every 5 days, every 6 days, 2 times a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, 4 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. Administration includes, but is not limited to, injection by any suitable route (e.g., parenteral, enteral, intravenous, subcutaneous, etc.). Methods of Manufacturing In one aspect, described herein, is a method of making an activatable immunocytokine, comprising providing an antibody or antigen binding fragment thereof (e.g., an antibody or antigen binding fragment provided herein), wherein the antibody comprises a reactive group (e.g., a conjugation handle), contacting the reactive group with a complementary reactive group attached to an Act-IL-18 polypeptide, and forming the activatable immunocytokine. The resulting composition is any of the compositions provided herein. In some embodiments, providing the antibody comprising the reactive group comprises attaching the reactive group to the antibody. In some embodiments, the reactive group is added site-specifically. In some embodiments, attaching the reactive group to the antibody comprises contacting the antibody with an affinity group comprising a reactive functionality which forms a bond with a specific residue of the antibody. In some embodiments, attaching the reactive group to the antibody comprises contacting the antibody with an enzyme. In some embodiments, the enzyme is configured to site-specifically attach the reactive group to a specific residue of the antibody. In some embodiments, the enzyme is glycosylation enzyme or a transglutaminase enzyme. -158- 49194109.1 ES Docket No.94917-0155.737601WO In some embodiments, the method further comprises attaching the complementary reactive group to the Act-IL-18 polypeptide. Definitions All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting. In this application, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. The terms “and / or” and “any combination thereof” and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof” can mean “A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.” The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use. The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value. Where -159- 49194109.1 ES Docket No.94917-0155.737601WO particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed. of as or or be “at 3, of is a ES Docket No.94917-0155.737601WO a lower value will have a higher binding affinity than a binding interaction with a higher value. For a protein-ligand interaction, KD is calculated according to the following formula: of or at so at ES Docket No.94917-0155.737601WO the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. Certain formulas and other illustrations provided herein depict triazole reaction products resulting from azide-alkyne cycloaddition reactions. While such formulas generally depict only a or or moieties are often recognized chemical entities embedded in or appended to a molecule. As used herein, “conjugation handle” refers to a reactive group capable of forming a bond upon contacting a complementary reactive group. In some instances, a conjugation handle preferably does not have a substantial reactivity with other molecules which do not comprise the -162- 49194109.1 ES Docket No.94917-0155.737601WO intended complementary reactive group. Non-limiting examples of conjugation handles, their respective complementary conjugation handles, and corresponding reaction products can be found in the table below. While table headings place certain reactive groups under the title “conjugation handle” or “complementary conjugation handle,” it is intended that any reference to a conjugation handle can instead encompass the complementary conjugation handles listed in the table (e.g., a trans-cyclooctene can be a conjugation handle, in which case tetrazine would be the complementary conjugation handle). In some instances, amine conjugation handles and conjugation handles complementary to amines are less preferable for use in biological systems owing to the ubiquitous presence of amines in biological systems and the increased likelihood for off-target conjugation. Table of Conjugation Handles Reaction Conjugation Handle Complementary Conjugation Handle Product alpha-halo-carbonyl (e.g., bromoacetamide), alpha- beta unsaturated carbonyl (e.g., maleimide, Sulfhydryl acrylamide) thioether alkyne (e.g., terminal alkyne, substituted cyclooctyne (e.g., dibenzocycloocytne (DBCO), Azide difluorocyclooctyne, bicyclo[6.1.0]nonyne, etc.) ) triazole Phosphine Azide / ester pair amide dihydropyrida Tetrazine trans-cyoclooctene zine Activated ester (e.g., N-hydroxysuccinimide ester, Amine pentaflurophenyl ester) amide isocyanate amine urea epoxide amine alkyl-amine hydroxyl amine aldehyde, ketone oxime hydrazide aldehyde, ketone hydrazone potassium acyl O-substituted hydroxylamine (e.g., O- trifluoroborate carbamoylhydroxylamine) amide Throughout the instant application, prefixes are used before the term “conjugation handle” to denote the functionality to which the conjugation handle is linked. For example, a “protein conjugation handle” is a conjugation handle attached to a protein (either directly or through a linker), an “antibody conjugation handle” is a conjugation handle attached to an antibody (either directly or through a linker), and a “linker conjugation handle” is a conjugation handle attached to a linker group (e.g., a bifunctional linker used to link a synthetic protein and an antibody). -163- 49194109.1 ES Docket No.94917-0155.737601WO The term “alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An an or of of ES Docket No.94917-0155.737601WO is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl- l(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[l.l.l]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. The term “heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkylene groups include, but are not limited to -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, - OCH2CH20CH2CH2O-, or - O CH2CH2 O CH2CH2 O CH2CH2O -. -165- 49194109.1 ES Docket No.94917-0155.737601WO The term “heteocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted. The term “heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, -166- 49194109.1 ES Docket No.94917-0155.737601WO indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and the 1 0- or a is - 2, D, ES Docket No.94917-0155.737601WO halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -C02H, -C02(Ci-C4alkyl), - C(=0)NH2, - C(=0)NH(C 1 -C4alkyl), -C(=0)N(Ci-C4alkyl)2, -S(=0)2NH2, -S(=0)2NH(Ci- C4alkyl), - S(=0)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1- C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=0)C1-C4alkyl, and -S(=0)2C1- C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and - OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0). As used herein, “AJICAPTMtechnology,” “AJICAPTMmethods,” and similar terms refer to systems and methods (currently produced by Ajinomoto Bio-Pharma Services (“Ajinomoto”)) for the site specific functionalization of antibodies and related molecules using affinity peptides to deliver the desired functionalization to the desired site. General protocols for the AJICAPTMmethodology are found at least in PCT Publication No. WO2018199337A1, PCT Publication No. WO2019240288A1, PCT Publication No. WO2019240287A1, PCT Publication No. WO2020090979A1, Matsuda et al., Mol. Pharmaceutics 2021, 18, 4058-4066, and Yamada et al., AJICAP: Affinity Peptide Mediated Regiodivergent Functionalization of Native Antibodies. Angew. Chem., Int. Ed. 2019, 58, 5592-5597, and in particular Examples 2-4 of US Patent Publication No. US20200190165A1. In some embodiments, such methodologies site specifically incorporate the desired functionalization at lysine residues at a position selected from position 246, position 248, position 288, position 290, and position 317 of an antibody Fc region (e.g., an IgG1 Fc region) (EU numbering). In some embodiments, the desired functionalization is incorporated at residue position 248 of an antibody Fc region (EU numbering). In some embodiments, position 248 corresponds to the 18thresidue in a human IgG CH2 region (EU numbering). Sequences (SEQ ID NOS) of IL-18 Polypeptides TABLE 3 -168- 49194109.1 ES Docket No.94917-0155.737601WO SEQ Modification Sequence ID NO: 1 Native YFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD sequence NAPRTIFIIS MYKDSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 2 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C68A, NAPRTIFIIS MYADSQPRGM AVTISVKAEK ISTLSCENKI E85C ISFKCMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 3 E6K, V11I, YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, K53A, NAPRTIFIIS MYADSQPRGM AVAISVKAEK ISTLSAENKI T63A, C68A, ISFKCMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY C76A, E85C, EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED C127A 4 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C68A, NAPRTIFIIS MYADSQPRGM AVTISVKAEK ISTLSCENKI M86C ISFKECNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 5 E6K, V11I, YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, K53A, NAPRTIFIIS MYADSQPRGM AVAISVKAEK ISTLSAENKI T63A, C68A, ISFKECNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY C76A, M86C, EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED C127A YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD 6 E6K, V11I, NAPRTIFIIS MYADSQPRGM AVAISVKAEK ISTLSAENKI C38A, K53A, ISFKEMNPPD NIKDTKSCII FFQRSVPGHD NKMQFESSSY T63A, C68A, EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED C76A, D98C, C127A 7 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C68A, NAPRTIFIIS MYADSQPRGM AVTISVKAEK ISTLSAENKI C76A, M86C, ISFKECNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY C127A EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 8 E6K, V11I, YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, K53A, NAPRTIFIIS MYADSQPRGM AVAISVKAEK ISTLSAENKI T63A, C68A, ISFKEMNPPD NIKDCKSDII FFQRSVPGHD NKMQFESSSY C76A, T95C, EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED C127A 9 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C68A, NAPRTIFIIS MYADSQPRGM AVTISVKAEK ISTLSCENKI D98C ISFKEMNPPD NIKDTKSCII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED -169- 49194109.1 ES Docket No.94917-0155.737601WO 10 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C68A, NAPRTIFIIS MYADSQPRGM AVTISVKAEK ISTLSAENKI C76A, D98C, ISFKEMNPPD NIKDTKSCII FFQRSVPGHD NKMQFESSSY C127A EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 11 E6K, V11I, YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, K53A, NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSAENKI C76A, C127A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 12 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, T63A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSAENKI C76A, C127A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 13 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD T63N NAPRTIFIIS MYADSQPRGM AVNISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 14 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S50A, T63N NAPRTIFIIA MYADSQPRGM AVNISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 15 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S50H, T63N NAPRTIFIIH MYADSQPRGM AVNISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 16 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD T63N, S65A NAPRTIFIIS MYADSQPRGM AVNIAVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 17 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S50H NAPRTIFIIH MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 18 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C68A NAPRTIFIIS MYADSQPRGM AVTISVKAEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 19 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD K79A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENAI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED -170- 49194109.1 ES Docket No.94917-0155.737601WO 20 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD R104A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENAI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 21 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD G108A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPAHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 22 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD H109A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGAD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 23 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD K112A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NAMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 24 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, T63A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSAENKI C76A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 25 E6K, C38Q, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDQRD K53A, T63A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSAENKI C76A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 26 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, T63A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSCENKI C127A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 27 E6K, C38Q, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDQRD K53A, T63A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSCENKI C127A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 28 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, T63A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSAENKI C76A, C127A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 29 E6K, V11I, YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, K53A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSCENKI T63A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED -171- 49194109.1 ES Docket No.94917-0155.737601WO 30 E6K, V11I, YFGKLKSKLS IIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, K53A, NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSAENKI T63A, C76A, ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY C127A EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 31 C38A, C76A, YFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD C127A NAPRTIFIIS MYKDSQPRGM AVTISVKCEK ISTLSAENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 32 C38AYFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD NAPRTIFIIS MYKDSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 33 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, T63A NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 34 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S55A NAPRTIFIIS MYADAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 35 Y01G, F02A, GAGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD E06K, M51G, NAPRTIFIIS GYAAAQPRGM AVAISVKCEK ISTLSCENKI K53A, D54A, ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY S55A, T63A EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 36 K53AYFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 37 S55AYFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYKDAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 38 E06KYFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYKDSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 39 E06K, K53AYFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED -172- 49194109.1 ES Docket No.94917-0155.737601WO 40 E06K, S55AYFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYKDAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 41 K53A, S55AYFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYADAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 42 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S55A, T63A NAPRTIFIIS MYADAQPRGM AVAISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 43 E06K, K53A, GFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S55A, Y01G NAPRTIFIIS MYADAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 44 E06K, K53A, YAGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S55A, F02A NAPRTIFIIS MYADAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 45 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S55A, D54A NAPRTIFIIS MYAAAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 46 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD S55A, M51G NAPRTIFIIS GYADAQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 47 C38S, C68S, YFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD C76S, C127S NAPRTIFIIS MYKDSQPRGM AVTISVKSEK ISTLSSENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED 48 C38S, C68S, YFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD C76S, C127S, NAPRTIFIIS MYKDSQPRGM AVTISVKSEC ISTLSSENKI K70C ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED 49 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD S55A, C38S, NAPRTIFIIS MYADAQPRGM AVTISVKSEC ISTLSSENKI C68S, C76S, ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY C127S, K70C EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED -173- 49194109.1 ES Docket No.94917-0155.737601WO 50 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD T63A NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 51 T63AYFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYKDSQPRGM AVAISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 52 E06K, T63AYFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYKDSQPRGM AVAISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 53 K53A, T63AYFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDCRD NAPRTIFIIS MYADSQPRGM AVAISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 54 E06K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD C38S, C68S, NAPRTIFIIS MYADSQPRGM AVTISVKSEC ISTLSSENKI C76S, C127S, ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY K70C EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED 55 K53A, T63A, YFGKLESKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD C38S, C68S, NAPRTIFIIS MYADSQPRGM AVAISVKSEC ISTLSSENKI C76S, C127S, ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY K70C EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED 56 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD C38S, C76S, NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSSENKI C127S ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED 57 E6K, C38S, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD K53A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 58 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDSRD C38S, C68S, NAPRTIFIIS MYADSQPRGM AVTISVKSEC ISTLSSENKI C76S, C127S, ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY K70C EGYFLASEKE RDLFKLILKK EDELGDRSIM FTVQNED 59 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED -174- 49194109.1 ES Docket No.94917-0155.737601WO 60 E6K, C38Q, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDQRD K53A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 61 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C76A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSAENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 62 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C127A NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSCENKI ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 63 E6K, C38A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD K53A, C76A, NAPRTIFIIS MYADSQPRGM AVTISVKCEK ISTLSAENKI C127A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLAAEKE RDLFKLILKK EDELGDRSIM FTVQNED 64 E6K, K53A, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDARD C38A, S55A, NAPRTIFIIS MYADAQPRGM AVAISVKCEK ISTLSCENKI T63A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 65 E6K, C38Q, YFGKLKSKLS VIRNLNDQVL FIDQGNRPLF EDMTDSDQRD K53A, S55A, NAPRTIFIIS MYADAQPRGM AVAISVKCEK ISTLSCENKI T63A ISFKEMNPPD NIKDTKSDII FFQRSVPGHD NKMQFESSSY EGYFLACEKE RDLFKLILKK EDELGDRSIM FTVQNED 66 E6K, K53A, YFGKLKSKLS VIRNLNDQV...

Claims

ES Docket No.94917-0155.737601WO CLAIMS 1. An activatable immunocytokine, comprising: an antibody or antigen binding fragment thereof; an activatable IL-18 (Act-IL-18) polypeptide, comprising: an artificial polypeptide attached to an IL-18 polypeptide, wherein the artificial polypeptide comprises a protease cleavage site, wherein cleavage at the protease cleavage site enhances an IL-18 related activity of the activatable immunocytokine; and a linker comprising: a first point of attachment to the antibody or antigen binding fragment thereof; and a second point of attachment to the Act-IL-18 polypeptide. 2 An activatable immunocytokine, comprising: an antibody or antigen binding fragment thereof; an activatable IL-18 (Act-IL-18) polypeptide, comprising: an artificial polypeptide attached to an IL-18 polypeptide, wherein the artificial polypeptide comprises a protease cleavage site, wherein cleavage at the protease cleavage site converts the Act-IL-18 polypeptide into an activated form of the IL-18 polypeptide with an enhanced IL-18 related activity; and a linker comprising: a first point of attachment to the antibody or antigen binding fragment thereof; and a second point of attachment to the Act-IL-18 polypeptide. 3 The activatable immunocytokine of claim 1 or 2, wherein the protease cleavage site is cleaved by a protease which is found at higher concentrations and / or demonstrates higher proteolytic activity within the tumor microenvironment relative to non-tumor tissue. 4 The activatable immunocytokine of any one of claims 1-3, wherein the protease is selected from: kallikrein, thrombin, chymase, carboxypeptidase A, an elastase, proteinase 3 (PR-3), granzyme M, urokinase plasminogen activator (uPA), a calpain, a matrix metalloproteinase (MMP), a disintegrin and metalloproteinase (ADAM), a fibroblast activation protein alpha (FAP), a matriptase, a plasminogen activator, a cathepsin, a caspase, a tryptase, and a tumor cell surface protease.ES Docket No.94917-0155.737601WO 5. The activatable immunocytokine of any one of claims 1-4, comprising a protease recognition sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a peptide sequence set forth in Table 2A or Table 2B, wherein the protease recognition sequence comprises the protease cleavage site. 6 The activatable immunocytokine of claim 5, wherein the protease recognition sequence comprises the amino acid sequence set forth in any one of SEQ ID NOs: 646, 647, 648, 649, 650, 651, 652, 653, 657, 658, or 659. 7 The activatable immunocytokine of any one of claims 1-5, wherein cleavage of the artificial polypeptide at the protease cleavage site leaves no amino acid residues of the artificial polypeptide attached to the IL-18 polypeptide, or wherein cleavage of the artificial polypeptide at the protease cleavage site leaves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues of the artificial polypeptide attached to the IL-18 polypeptide. 8 The activatable immunocytokine of any one of claims 1-7, wherein the artificial polypeptide comprises multiple protease cleavage sites. 9 The activatable immunocytokine of claim 8, wherein the artificial polypeptide comprises 2, 3, or 4 protease cleavage sites. 10 The activatable immunocytokine of any one of claims 1-9, wherein the IL-18 polypeptide comprises substitutions of one or more amino acids at or near the N- or C-terminus of the IL- 18 polypeptide which form part of a recognition sequence for the protease cleavage site. 11 The activatable immunocytokine of claim 10, wherein the substitutions of the one or more amino acids at or near the N- or C-terminus of the IL-18 polypeptide comprises amino acid substitutions of residues 1, 2, and / or 3 of the IL-18 polypeptide, wherein residue position numbering is based on SEQ ID NO: 1 as a reference sequence. 12 The activatable immunocytokine of claim 11, wherein the artificial polypeptide comprises a blocking moiety. 13 The activatable immunocytokine of claim 12, wherein the artificial polypeptide comprises a linking peptide between the specific cleavage site and the blocking moiety. 14 The activatable immunocytokine of claim 12 or 13, wherein the blocking moiety is positioned such that cleavage at the protease cleavage site releases the blocking moiety from the IL-18 polypeptide.ES Docket No.94917-0155.737601WO 15. The activatable immunocytokine of any one of claims 12-14, wherein the blocking moiety comprises an IL-18 propeptide or a portion thereof, or a variant thereof, preferably wherein the IL-18 propeptide is a human IL-18 propeptide or a variant thereof.

16. The activatable immunocytokine of claim 15 wherein the IL-18 propeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO:

89.

17. The activatable immunocytokine of any one of claims 15 or 16, wherein the IL-18 propeptide comprises a substitution of the cysteine residue in SEQ ID NO:

89.

18. The activatable immunocytokine of any one of claims 16-18, wherein the IL-18 propeptide comprises the sequence set forth in SEQ ID NO: 89, 91, 96, or 97.

19. The activatable immunocytokine of any one of claims 12-18, wherein the Act-IL-18 polypeptide has a structure BM-CS-IL-18, wherein IL-18 is the IL-18 polypeptide, CS is a moiety comprising the specific cleavage site, and BM is the blocking moiety, and wherein the orientations is shown in an N-terminal to C-terminal order.

20. The activatable immunocytokine of any one of claims 1-19, wherein the artificial polypeptide is connected to the N-terminus of the IL-18 polypeptide.

21. The activatable immunocytokine of any one of claims 12-14, wherein the blocking moiety comprises a domain of an IL-18 receptor subunit or a portion thereof, or a derivative thereof.

22. The activatable immunocytokine of claim 21, wherein the domain of the IL-18 receptor subunit comprises the D3 domain of the IL-18 receptor alpha subunit, or a variant thereof.

23. The activatable immunocytokine claim 21 or 22, wherein the blocking moiety comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO:

93.

24. The activatable immunocytokine of any one of claims 1-14 or 21-23, wherein the artificial polypeptide is connected to the C-terminus of the IL-18 polypeptide.

25. The activatable immunocytokine of any one of claims 1-24, wherein the IL-18 polypeptide displays reduced binding to IL-18 binding protein (IL-18BP) compared to WT IL-18.

26. The activatable immunocytokine of any one of claims 1-25, wherein the IL-18 polypeptide displays enhanced binding to IL-18R or ability to activate IL-18R.ES Docket No.94917-0155.737601WO 27. The activatable immunocytokine of any one of claims 1-26, wherein the active form of the IL- 18 polypeptide displays a binding to IL-18R or ability to activate IL-18R which is reduced by at most 100-fold relative to WT IL-18. 8 The activatable immunocytokine of any one of claims 1-27, wherein the IL-18 polypeptide comprises one or more modifications to the sequence set forth in SEQ ID NO:

1. an an the 1,ES Docket No.94917-0155.737601WO 38. The activatable immunocytokine of claim 28, wherein the IL-18 polypeptide comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 79-83 or 84-86, optionally with substitutions at residues 1, 2, and / or 3 of the sequence to facilitate enhanced cleavage of the protease cleavage site.

39. The activatable immunocytokine of any one of claims 1-38, wherein the enhanced activity is a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is at least 1,000-fold lower, 2,000-fold lower 5,000-fold lower, 10,000-fold lower, 15,000-fold- lower, or 20,000-fold lower than the activated form of the IL-18 polypeptide.

40. The activatable immunocytokine of any one of claims 1-38, wherein the enhanced activity is a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is from about 10-fold lower to about 100-fold lower.

41. The activatable immunocytokine e of any one of claims 1-40, wherein the enhanced activity is a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is within about 10-fold of the IL-18 polypeptide.

42. The activatable immunocytokine of any one of claims 1-41, wherein the enhanced activity is a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is less than about 10-fold higher than that of WT IL-18.

43. The activatable immunocytokine of any one of claims 1-42, wherein the enhanced activity is a half-maximal effective concentration (EC50) for IL-18 receptor signaling activity which is at least 10-fold greater than WT IL-18.

44. The activatable immunocytokine of any one of claims 1-43, wherein the linker comprises a polymer.

45. The immunocytokine composition of claim 44, wherein the polymer comprises a water- soluble polymer.

46. The immunocytokine composition of claim 45, wherein the water-soluble polymer comprises poly(alkylene oxide), polysaccharide, poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), or a combination thereof 47. The immunocytokine composition of any one of claims 44-46, wherein the polymer comprises poly(ethylene glycol).

48. The immunocytokine composition of any of claims 44-47, wherein the polymer has a molecular weight of from about 100 Da to about 2000 Da.ES Docket No.94917-0155.737601WO 49. The activatable immunocytokine composition of any one of the preceding claims, wherein the second point of attachment is at a position which is not the N- or C-terminus of the IL-18 polypeptide, or wherein the second point of attachment is to the C-terminus of the IL-18 polypeptide, optionally wherein the linker is attached via sortase.

50. The activatable immunocytokine of any one of the preceding claims, wherein the second point of attachment is at residue 38, 68, 69, 70, 76, 78, 85, 86, 95, 98, 121, 127, or 144 of the IL-18 polypeptide, wherein residue position numbering is based on SEQ ID NO: 1 as a reference sequence.

51. The activatable immunocytokine of any one of the preceding claims, wherein the second point of attachment is at residue 68 of the IL-18 polypeptide, wherein residue position numbering is based on SEQ ID NO: 1 as a reference sequence.

52. The activatable immunocytokine of any one of the preceding claims, wherein the first point of attachment is at an amino acid residue in an Fc region of the antibody or antigen binding fragment.

53. The activatable immunocytokine of claim 52, wherein the first point of attachment is at a position of a K246 amino acid residue, a K248 amino acid residue, a K288 amino acid residue, a K290 amino acid residue, or a K317 amino acid residue of the Fc region (Eu numbering).

54. The activatable immunocytokine of claim 53, wherein the first point of attachment is at the K248 amino acid residue.

55. The activatable immunocytokine of any one of claims 1-54, wherein the antibody or antigen binding fragment thereof is a monoclonal antibody, a humanized antibody, a grafted antibody, a chimeric antibody, a human antibody, a de-immunized antibody, or a bispecific antibody.

56. The activatable immunocytokine of any one of claims 1-54, wherein the antibody or antigen binding fragment thereof comprises a Fab, a Fab', a F(ab')2, a bispecific F(ab')2, a trispecific F(ab')2, a variable fragment (Fv), a single chain variable fragment (scFv), a dsFv, a bispecific scFv, a variable heavy domain, a variable light domain, a variable NAR domain, bispecific scFv, an AVIMER®, a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a minibody, a maxibody, a camelid, a VHH, a minibody, an intrabody, fusion proteins comprising an antibody portion (a domain antibody), a single chain binding polypeptide, a scFv-Fc, a Fab-Fc, a bispecific T cell engager (BiTE), a tetravalent tandem diabody (TandAb), a Dual-Affinity Re-targeting Antibody (DART), a bispecific antibody (bscAb), a singleES Docket No.94917-0155.737601WO domain antibody (sdAb), a fusion protein, or a bispecific disulfide-stabilized Fv antibody fragment (dsFv–dsFv′).

57. The activatable immunocytokine of any one of claims 1-56, wherein the antibody or antigen binding fragment thereof comprises an IgG, an IgM, an IgE, an IgA, an IgD, or is derived therefrom.

58. The activatable immunocytokine of any one of claims 1-57, wherein the antibody or antigen binding fragment thereof comprises the IgG, and wherein the IgG is an IgG1, an IgG4, or a derivative thereof.

59. The activatable immunocytokine composition of any one of claims 1-58, wherein the antibody or antigen binding fragment thereof binds specifically to an immune associated antigen.

60. The activatable immunocytokine of claim 59, wherein the immune associated antigen is 4- IBB, CD3, CCR8, CD8A, CD8B, CD16A, CD28, CD80, CD86, CD96, CD226, CTLA-4, D40, GITR, ICOS, LAG-3, MHCI, MHCII, NKG2A, NKG2D, NKp30, NKp44, NKp46, OX40, PD-1, PD-L1, PD-L2, SIRPA, TCR, TIGIT, TIM-3, or VISTA.

61. The activatable immunocytokine of claim 59 or 60, wherein the immune associated antigen is PD-1.

62. The activatable immunocytokine of claim 61, wherein the antibody or antigen binding fragment thereof comprises Tislelizumab, Sintilimab, Toripalimab, Terepril, Camrelizumab, Cemiplimab, Pembrolizumab, Nivolumab, Prolgolimab, Penpulimab, Zimberelimab, Balstilimab, Genolimzumab, Geptanolimab, Dostarlimab, Serplulimab, Retifanlimab, Sasanlimab, Spartalizumab, Cetrelimab, Tebotelimab, Cadonilimab, Pidilizumab, LZM-009, or Budigalimab, or a modified version thereof.

63. The activatable immunocytokine of claim 61 or 62, wherein the antibody or antigen binding fragment thereof comprises LZM-009.

64. The activatable immunocytokine of claim 59, wherein immune associated antigen is PD-L1.

65. The activatable immunocytokine of claim 64, wherein the antibody or antigen binding fragment thereof comprises Avelumab, Durvalumab, Atezolizumab, Sugemalimab, Sasanlimab, Envafolimab, Lodapolimab, or Cosibelimab, or a modified version thereof.

66. The activatable immunocytokine of claim 65, wherein the antibody or antigen binding fragment thereof comprises Durvalumab.ES Docket No.94917-0155.737601WO 67. The activatable immunocytokine of any one of claims 1-66, further comprising a second Act- IL-18 polypeptide attached to the antigen or antigen binding fragment thereof by a second linker.

68. An activatable IL-18 (Act-IL-18) polypeptide, comprising an artificial polypeptide attached to an IL-18 polypeptide, wherein the artificial polypeptide comprises a protease cleavage site, wherein cleavage at the protease cleavage site enhances an activity of the IL-18 polypeptide, and wherein the Act-IL-18 polypeptide comprises a blocking moiety attached to the IL-18 polypeptide through the protease cleavage site.

69. An activatable IL-18 (Act-IL-18) polypeptide having a structure BM-CS-IL-18; BM-LP1-CS-IL-18; BM-LP1-CS-LP2-IL-18; or BM-CS-LP1-IL-18; wherein IL-18 is an IL-18 polypeptide, CS is a moiety comprising a specific cleavage site (e.g., a protease recognition sequence), LP1 is a first linking peptide, LP2 is a second linking peptide, and BM is a blocking moiety, and wherein the orientations are shown in an N-terminal to C- terminal order, preferably wherein the Act-IL-18 polypeptide as a structure BM-CS-IL-18..

70. The Act-IL-18 polypeptide of claim 68 or 69, wherein the blocking moiety the blocking moiety comprises an IL-18 propeptide or a portion thereof, or a variant thereof, preferably wherein the IL-18 propeptide is a human IL-18 propeptide or a variant thereof.

71. The Act-IL-18 polypeptide of claim 70 wherein the IL-18 propeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO:

89.

72. The Act-IL-18 polypeptide of any one of claims 70 or 71, wherein the IL-18 propeptide comprises a substitution of the cysteine residue in SEQ ID NO:

89.

73. The Act-IL-18 polypeptide of any one of claims 70-72, wherein the IL-18 propeptide comprises the sequence set forth in SEQ ID NO: 89, 91, 96, or 97.

74. The Act-IL-18 polypeptide of any one of claims 68-73, wherein the IL-18 polypeptide comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the sequence set forth in SEQ ID NO: 1.ES Docket No.94917-0155.737601WO 75. The Act-IL-18 polypeptide of any one of claims 68-74, wherein the IL-18 polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-67 or 79-86, or another IL- 18 polypeptide as described herein.

76. The Act-IL-18 polypeptide of any one of claims 68-75, wherein the specific cleavage site is comprised within a protease recognition sequence provided Table 2B.

77. The Act- IL-18 polypeptide of any one of claims 68-76, wherein the specific cleavage site is the protease recognition sequence comprises the amino acid sequence set forth in any one of SEQ ID NOs: 646, 647, 648, 649, 650, 651, 652, 653, 657, 658, or 659.

78. A pharmaceutical composition comprising: a) an activatable immunocytokine of any one of claims 1-67 or an Act-IL-18 polypeptide of anyone of claims 68-77; and b) a pharmaceutically acceptable carrier or excipient.

79. A method of treating cancer in a subject in need thereof, comprising: administering to the subject a pharmaceutically effective amount of an activatable immunocytokine of any one of claims 1-67, an Act-IL-18 polypeptide of any one of claims 68- 77, or a pharmaceutical composition of claim 78.

80. The method of claim 79, wherein the cancer is a solid cancer.

81. The method of claim 80, wherein the solid cancer is adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid cancer, cervical cancer, colorectal cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal stromal tumor, germ cell cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine cancer, oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, pediatric cancer, penile cancer, pituitary cancer, prostate cancer, skin cancer, soft tissue cancer, spinal cord cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, ureteral cancer, uterine cancer, vaginal cancer, or vulvar cancer.

82. The method of claim 80, wherein the solid cancer is metastatic renal cell carcinoma or melanoma.

83. The method of claim 80, wherein the solid cancer is a carcinoma or a sarcoma.

84. The method of claim 79, wherein the cancer is a blood cancer.ES Docket No.94917-0155.737601WO 85. The method of claim 84, the blood cancer is leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, an AIDS-related lymphoma, multiple myeloma, plasmacytoma, post- transplantation lymphoproliferative disorder, or Waldenstrom macroglobulinemia.

86. The method of any one of claims 79-85, further comprising reconstituting a lyophilized form of the activatable immunocytokine or the pharmaceutical composition.

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