Masked il-12 cytokines and their cleavage products

Abstract

The present invention relates to masked IL-12 cytokines, comprising an IL-12 cytokine or functional fragment thereof, a masking moiety and a proteolytically cleavable linker. The masking moiety masks the IL-12 cytokine or functional fragment thereof thereby reducing or preventing binding of the IL-cytokine or functional fragment thereof to its cognate receptor, but upon proteolytic cleavage of the cleavable linker at a target site, the IL-12 cytokine or functional fragment thereof becomes activated, which renders it capable or more capable of binding to its cognate receptor.

Description

MASKED IL-12 CYTOKINES AND THEIR CLEAVAGE PRODUCTSCROSS-REFERENCE TO RELATE® APPLICATIONSThis application claims the priority benefit of U.S. Provisional Application Serial Nos. 63 / 003,842, filed April 1, 2020; 63 / 118,579, filed November 25, 2020; and 63 / 127,893, filed December 18, 2020; each of which is incorporated herein by reference in its entirety.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILEThe content of the following submission on ASCII text file is incorporated herein by reference in its entirety': a computer readable form (CRF) of the Sequence Listing (file name: 737762002840SEQLTST.TXT, date recorded: March 26, 2021, size: 1,000 KB).FIELDThis invention relates to masked IL-12 cytokines and methods related to the use and manufacture of tire same. This invention also relates to cleavage products of said masked IL- i 2 cytokines, and methods related to the use of the same.BACKGROUND Cancer is the second leading cause of death in the United States, accounting for more deaths than the next five leading causes (chronic respiratory disease, stroke, accidents, Alzheimer’s disease and diabetes). While great strides have been made especially with targeted therapies, there remains a great deal of work to do in this space. Immunotherapy and a branch of tins field, immuno-oncology, is creating viable and exciting therapeutic options for treating malignancies. Specifically, it is now recognized that one hallmark of cancer is immune evasion and significant efforts have identified targets and developed therapies to these targets to reactivate the immune system to recognize and treat cancer.Cytokines can be classified in a variety of ways, such as based on their three-dimensional structure. Some cytokines are classified as being heterodimeric. Examples of heterodi meric cytokines include IL-12 and IL-23. IL-12 cytokine is a heterodimer comprising p35 and p40 sub-units.Cytokine therapy is an effective strategy for stimulating the immune system to induce anti-tumor cytotoxicity. In particular, aldesleukin, a recombinant form of interleukin-2 (IL-2), lias been approved by the FDA for the treatment of metastatic renal cell carcinoma and melanoma. Unfortunately, cytokines that are administered to patients generally have a very short half-life, thereby requiring frequent dosing. For instance, the product label of aldesleukin, marketed under the brand name Proleukin, states that the drug was shown to have a half-life of 85 minutes in patients who received a 5- minute intravenous (IV) infusion. In addition, admini tration of high doses of cytokine can cause adverse health outcomes, such as vascular leakage, through systemic immune activation. These findings illustrate the need for developing IL-2 cytokine therapeutics that effectively target tumors without the side effects associated with systemic immune activation.Provided herein are masked EL- 12 cytokines, cleavage products of said masked 11,-12 cytokines, and compositions thereof and methods of use thereof for addressing this need. SUMMARYThe disclosed invention relates to IL-I2 cytokines or functional fragments thereof that are engineered to be masked by a masking moiety at one or more receptor binding site(s) of the IL-12 cytokine or functional fragment thereof. The IL-12 cytokines are engineered to be aetivatable by a protease at a target site, such as in a tumor microenvironment, by including a proteolyticaliy cleavable linker. In the masked cytokine construct, the masking moiety reduces or prevents binding of the IL-12 cytokine or functional fragment thereof to its cognate receptor. Upon proteolytic cleavage of the cleavable linker at the target site, the IL- 12 cytokine or functional fragment thereof becomes activated, which renders it capable or more capable of binding to its cognate receptor.Provided herein is a masked IL-12 cytokine comprising a protein heterodimer comprising: a first polypeptide chain comprising:N’ HL1-LI-MM C’ and a second pol eptide chain comprising: N’ HL2-L2-C C’ where HL I is a first half life extension domain, L I is a first linker, MM is a masking moiet , HL2 is a second half life extension domain, L2 is a second linker, and C is an IL-12 cytokine or functional fragment thereof, wherein the first half-life extension domain is associated with the second half-life extension domain, and wherein one of the first linker or the second linker comprises a proteolyticaliy cleavable peptide.in some embodiments, the IL-12 polypeptide or functional fragment thereof comprises an ]L-12p40 polypeptide or functional fragment thereof covalently linked to an IL-12p35 polypeptide or functional fragment thereof.In some embodiments, the 1L-I2p40 - 1L-I2p35 linker is between 5 and 20 amino acids in length.In some embodiments, the IL-12p40 - IL-12p35 linker is rich in amino acid residues G and S. In some embodiments, the IL-12p40 - TL-12p35 linker comprises SEQ ID NO: 3.In some embodiments, the IL-12p40 polypeptide comprises SEQ ID NO: 1 or an amino acid sequence having at least one amino acid modification as compared to the amino acid sequence of SEQ ID NO: 1. in some embodiments, the 1L-I2p40 polypeptide comprises SEQ ID NO: 1.In some embodiments, the IL-12p40 polypeptide comprises at least one amino acid modification to the GAG-binding domain (KSKREKKDRV) as compared to the a ino acid sequence of SEQ ID NO: 1. in some embodiments, the IL-12p40 polypeptide comprises SEQ ID NO: 57.In some embodiments, the IL~12p40 polypeptide comprises SEQ ID NO: 58In some embodiments, the IL-12p40 polypeptide comprises an amino acid sequence having one or more c steine substitution mutations as compared to the amino acid sequence of SEQ ID NO: 1.In some embodiments, the lL-12p4G polypeptide comprises SEQ ID NO: 59.In some embodiments, the 1L-I2p40 polypeptide comprises SEQ ID NO: 60. In some embodiments, the IL-12p35 polypeptide comprises SEQ ID NO: 2 or an amino acid sequence having at least one ami no acid modification as compared to the amino acid sequence of SEQ ID NO: 2.In some embodiments, the TL-12p35 polypeptide comprises SEQ ID NO: 2. in some embodiments, the IL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 4. in some embodiments, the IL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 61. in some embodiments, the IL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 62.in some embodiments, the IL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 63.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 64. in some embodiments, the masking moiety comprises an IL-12 cytokine receptor, or a subunit or functional fragment thereof.In some embodiments, the masking moiety comprises the extracellular domain of human iL-12Rf$l or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity' to IL-12.In some embodiments, the masking moiety comprises residues 24 to 237 of human TL-12R[31, namely a sequence having SEQ ID NO: 5. In some embodiments, the masking moiety comprises residues 24 to 545 of human IL-llRpl, namely a sequence having SEQ ID NO: 6.In some embodiments, the masking moiety comprises the extracellular domain of human IL-12R[32 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12.In some embodiments, the masking moiety comprises residues 24 to 212 of human !L-12Rp2, namely a sequence having SEQ ID NO: 7.In some embodiments, the masking moiety comprises residues 24 to 222 of human IE-I2Kb2, namely a sequence having SEQ ID NO: 8, or the masking moiety comprises residues 24 to 227 of hitman IL-I2RP2, namely a sequence having SEQ ID NO: 11. in some embodiments, the masking moiety comprises residues 24 to 319 of human IL-12R$2, namely a sequence having SEQ ID NO: 9.In some embodiments, the masking moiety comprises at least one amino acid modification as compared to the sequence of SEQ ID NO: 9, optionally wherein said modifications are cysteine substitution mutations.In some embodiments, the masking moiety comprises SEQ ID NO: 65.In some embodiments, the masking moiety comprises residues 24 to 622 of human !L-12R[32, namely a sequence having SEQ ID NO: 10.in some embodiments, the cleavable peptide is from 6 to 10 amino acids in length. in some embodiments, the cleavable peptide comprises an amino acid sequence of SEQ ID NO: 15. in some embodiments, the cleavable peptide comprises an amino acid sequence of SEQ ID NO: 41. in some embodiments, the cleavable peptide comprises an amino acid sequence of SEQ ID NO: 42. in some embodiments, the cleavable peptide comprises an amino acid sequence of SEQ ID NO: 43In some embodiments, the cleavable peptide comprises an amino acid sequence of SEQ ID NO: 44In some embodiments, the cleavable peptide comprises an amino acid sequence of SEQ ID NO: 45In some embodiments, the first polypeptide chain comprises:N’ HLl-non-deavable LI -MM C and the second polypeptide chain comprisesN’ HL2- eavable L2-C C’ in some embodiments, the non-cleavable linker is between 3 and 18 amino acids in length.In some embodiments, the non-cleavable linker is between 3 and 15 amino acids in length.In some embodiments, tine non-cleavable linker is rich in amino acid residues G and S. in some embodiments, the non-cleavable linker includes [(G)„S], where n=4 or 5. in some embodiments, the non-cieavable linker comprises an amino acid sequence as shown in SEQ ID NO: 12.In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 13.In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 14.In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 54 (GGSGGSGGSGGSGGSSGP).in some embodiments, the non-cieavable linker comprises an amino add sequence as shown in SEQ ID NO: 55 (PGGSGP). in some embodiments, the non-cieavable linker comprises an ammo acid sequence as shown in SEQ ID NO: 56 (GGSPG). in some embodiments, the cleavable linker comprises a proieolytically cleavable peptide (CP) flanked on both sides by a spacer domain (SD): SD1-CP-SD2 where SD1 and 8D2 are different, such that the first polypeptide chain comprises:N’HLl-non-cleavable Ll-MM C’ and the second polypeptide chain comprises:N'' HL2- SD1-CP-SD2 -C C’In some embodiments, the first spacer domain (SD1) is between 3 and 10 amino acids in lengthIn some embodiments, SD1 comprises SEQ ID NO: 16 in some embodiments, SD1 comprises SEQ ID NO: 17.In some embodiments, the second spacer domain (SD2) is between 3 and 6 amino acids in length. in some embodiments, SD2 comprises SEQ ID NO: 18.In some embodiments, the proieolytically cleavable linker comprises SD1-CP-SD2 where SD1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP has an amino acid sequence as shown in SEQ ID NO: 44 and SD2 lias an amino acid sequence as shown in SEQ ID NO: 18.In some embodiments, the proieolytically cleavable linker comprises SD1-CP-SD2 where SD1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP lias an amino acid sequence as shown in SEQ ID NO: 45 and SD2 lias an amino acid sequence as shown in SEQ ID NO: 18. in some embodiments, the cleavable linker comprises SEQ ID NO: 19.In some embodiments, the cleavable linker comprises SEQ ID NO: 20. in some embodiments, the cleavable linker comprises SEQ ID NO: 46. (GGSGGSMPYDLYHPSGP) In some embodiments, the cleavable linker comprises SEQ ID NO: 47.(GGSGGSGG8MPYDLYHPSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 48. (GGSGGSDSGGFMLTSGP) in some embodiments, the cleavable linker comprises SEQ ID NO: 49(GGS GG S GGSD S GGFMLT S GP)In some embodiments, the cleavable linker comprises SEQ ID NO: 50 (GGSGGSRAAAVKSPSGP) In some embodiments, the cleavable linker comprises SEQ ID NO: 51.(GGSGG S G GSRAAAVKSP S GP)In some embodiments, the cleavable linker comprises SEQ ID NO: 52, (GGSGGSISSGLLSGRSSGP) In some embodiments, the cleavable linker comprises SEQ ID NO: 53. (GGSGGSGGSISSGLLSGRSSGP)In some embodiments, the first half-life extension domain comprises a first IgGl Fc domain or a fragment thereof and she second half-life extension domain comprises a second IgGl Fe domain or a fragment thereof.In some embodiments, the first and' or second Fc domains each contain one or more modifications that promote tire non-covalent association of the first and the second half-life extension domains. in some embodiments, the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38 A; Y407V, N297A and 1253 A) and the second half-life extension domain comprises SEQ ID NO: 28(S354C, T366W, N297A and I253A).in some embodiments, the first polypeptide chain comprises an amino acid sequence of SEQ ID NO:34 and a second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 40.Provided herein is a cleavage product capable of binding to IL-12R, the cleavage product comprising an 1L-12 cytokine or functional fragment thereof, preparahle by proteolytic cleavage of the cleavable peptide in a masked IL-12 cytokine as defined in of any one of the statements or embodiments described herein.Provided herein is a cleavage product of a masked IL-12 cytokine, where the cleavage product is capable of binding to IL-12R, the cleavage product comprising a polypeptide comprising:PCP-SD2-C wherein PCP is a portion of a proteolytically cleavable peptide; SD2 is a spacer domain; and C is an IL-12 cytokine or functional fragment thereof.In some embodiments, PCP is a portion of a proteol tically cleavable peptide as described herein.In some embodiments, SD2 is a spacer domain as described herein. in some embodiments, C is an IL-12 cytokine or functional fragment thereof as described herein in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 29In some embodiments, tire cleavage product comprises an amino acid sequence of SEQ ID NO: 29.Provided herein is a nucleic acid encoding any one of the masked IL-12 cytokines described herein.Provided herein is a nucleic acid encoding one of the chains of any one of the masked IL-12 cytokines described herein.Provided herein is a vector comprising a nucleic acid described herein.Provided herein is a vector comprising a nucleic acid encoding a masked IL-12 cytokine described herein.Provided herein is a vector comprising a nucleic acid encoding one of the drains of a masked IL-12 cytokine described herein.Provided herein is a host ceil comprising a nucleic acid described herein.in one embodiment, the host cell is a HEK cell. In another embodiment, the host cell is a CHO cell.Provided herein is a composition comprising any one of the masked lL-12 cytokines described herein.Provided herein is a pharmaceutical composition comprising any one of the masked IL-12 cytokines described herein and a pharmaceutically acceptable earner.In some embodiments, the pharmaceutical composition is in single unit dosage form.In some embodiments, the pharmaceutical composition is formulated for intravenous administration and is in single unit dosage form.In some embodiments, the pharmaceutical composition is formulated for injection and is in single unit dosage form. in some embodiments, the pharmaceutical composition is a liquid and is in single unit dosage form.Provided herein is a kit comprising a masked IL-12 cytokine as described herein, or a composition described herein, or a pharmaceutical composition described herein.Provided herein is a method of producing a masked IL-12 cytokine as described herein comprising culturing a host cell described herein under a condition that produces the masked IL-12 cytokine. Provided herein is a nucleic acid encoding a cleavage product described herein.Provided herein is a composition comprising a cleavage product described herein.Provided herein is a pharmaceutical composition comprising a cleavage product described herein, and a pharmaceutically acceptable carrier.Provided herein is a masked IL-12 cytokine described herein for use in medicine.Provided herein is a cleavage product described herein for use in medicine.Provided herein is a method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a masked IL-12 cytokine described herein.Provided herein is a method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a composition described herein.Provided herein is a method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition described herein.Provided herein is a method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a masked IL-12 cytokine described herein, whereby the masked cytokine is proteoiytically cleaved in vivo to produce a cleavage product described herniaProvided herein is a method of treating or preventing cancer in a subject the method comprising a step of producing a cleavage product in vivo that is capable of binding to its cognate receptor, wherein the cleavage product is described herein in some embodiments, the cancer is a solid tumor.Provided herein is a masked IL- 12 cytokine described herein for use in treating or preventing cancer.Provided herein is a masked IL- 12 cytokine described herein for use in a method of treating or preventing cancer, the method comprising administering to the subject an effective amount of the masked IL-12 cytokine, whereby the masked cytokine is proteoiytically cleaved in vivo to produce a cleavage product as described herein.In some embodiments, the cancer is a solid tumor.Provided herein is a cleavage product described herein for use in treating or preventing cancer.Provided herein is a cleavage product described herein for use in a method of treating or preventing cancer, the method comprising a step of administering a masked cytokine described herein to a patient, thereby producing the cleavage product by proteolytic cleavage of the masked cytokine in vivo.Provided herein is a cleav age product described herein for use in a method of treating or preventing cancer in a subject, the method comprising a step of producing the cleavage product by in vivo proteolytic cleavage from a masked cytokine described herein that lias been administered to the subject. in some embodiments, the cancer is a solid tumor.Provided herein is a pharmaceutical composition described herein for use in healing or preventing cancer.In some embodiments, the cancer is a solid tumor. A BREIF DESCRIPTION OF THE DRAWINGSFIG. 1 shows the structure of exemplary embodiments of a masked cytokine that includes a masking moiety, a cytokine or functional fragment thereof (“cytokine”), a half-life extension domain, and a first linker that includes a first cleavable peptide (‘1CP”), a first N-terminal spacer domain (“1NSD”), and a first C-teiminal spacer domain (“1CSD”). These exemplar}' embodiments also include a second linker that includes a second cleavable peptide (“2CP”), a second N- terminal spacer domain (“2NSD”), and a second C-terminai spacer domain (“2CSD”). As shown by the arrow's, while the exemplary embodiments shows the masking moiety' linke to the first linker, and the cytokine or functional fragment thereof is linked to the first linker and the second linker, the masking moiety and the cytokine or functional fragment thereof can be interchanged such that the cytokine or functional fragment thereof is linked to the first linker, and the masking moiety is linked to the first lin er and the second linker. FIG. 1 shows the structure of an exemplary' embodiment of a masked cytokine as a monomer.FIG. 2 shows die structure of an exemplary embodiment of a masked cytokine that includes a masking moiety, a cytokine or functional fragment thereof (“cytokine”), a first half-life extension domain, and a second half-life extension domain. The exemplary' embodiment shown in FIG. 2 also includes a first linker that includes a first cleavable peptide (“ 1CP”), a first N-terminal spacer domain (“ 1NSD”), and a first C-terminal spacer domain (“ lCSD”), and a second linker that includes a second cleavable peptide (“2CP”), a second N-terminal spacer domain (“2NSD”), and a second C- terminal spacer domain (“2C8D”). The exemplary first and second half-life extension domains include “knobs into holes” modifications that promote the association of the first half-life extension domain with the second half-life extension domain, as shown by the “hole" in the first half-life extension domain and the “knob” in the second half-life extension domain. The first half-life extension domain and the second half-life extension domain are also shown as associating, at least in part, due to the formation of disulfide bonds it is to be understood that although the “hole” is depicted as part of the first half-life extension domain (linked to the masking moiety ) and the “knob” is depicted as part of the second half-life extension domai n (linked to tire cytokine), the “hole” and the “knob” can alternatively be included in the second half-life extension domain and the first half-life extension domain, respectively, so that the “hole” is a part of the second half-life extension domain (linked to the cytokine) and the “knob” is part of the first half-life extension domain (linked to masking moiety).FIGs. 3A-3B show exemplar,' embodiments of masked cytokines prior to (left) and after (right) cleavageby a protease, such as at the tumor microenvironment. FIGs. 3A-3B show exemplary embodiments of a masked IL-2 cytokine. Cleavage by a protease releases a masking moiety (e.g., IL-2.R}3, as shown in FIG. 3B), or releases an IL-2 (FIG. 3A).FIG 4 shows SDS-PAGE analysis on flow-through (FT) samples (i.e., proteins that did not hind to the Protein A column) and the eluted (E) samples (i.e., proteins that bound to the Protein A column and were eluted from it) following production and purification of 1L~2 constructs (AK304, AK305, AK307, AK308. AK309. AK310, AK31 I, AK312, AK3I3, AK3I4, and AK315).FIGs. 5A-SD show results from SPR analysis that tested the binding of an exemplary masked IL-2 polypeptide eonstruets (AK168), or a rWL2 control, to CD25-Fc. FIG, 5A shows the interaction between AK168 and CD25-Fc, FIG. SB shows the interaction between AK168 activated with MMP and CD25-Fc, and FIG.5C shows the interaction between a recombinant human IL-2 (rhIL-2) control and CD25-Fc. FIG. SB provides a table summarizing the data obtained for the association constant (ka), dissociation constant (kd), equilibrium dissociation constant (KD), as well as the Chi2 value and IJ -value for each interaction FIGs, 6A-6D shows results from SPR analysis that tested the binding of an exemplaiy masked IL-2 polypeptide constructs (AK111), or a rhIL-2 control, to CD 122-Fc. FIG. 6A shows the interaction between AK111 and CD 122-Fc, FIG, 6B shows the interaction between AK 111 activated with protease and CD 122-Fc, and FIG. 6C shows the interaction between a recombinant human IL-2 (rhJL-2) control and CD 122-Fc. FIG. 6D provides a table summarizing the data obtained for the association constant (ka), dissociation constant (kd), equilibrium dissociation constant (KD), as well as the CM2 value and U- value for each interaction.FIG. 7 A shows an exemplar)7embodiment of a masked cytokines prior to (left) and after (right) cleavage by a protease, such as at the tumor microenvironment. FIG. 7B show's SDS-PAGE analysis of an exemplary masked IL-2 polypeptide construct that was incubated in the absence (left lane) or presence (right lane) of the MMP10 protease, which demonstrates the release of IL-2 from the Fc portion.FIGs. 8A-8D show STATS activation (%) inPBMCs treated with the construct AK032, AK035, AK041, or rhlL-2 as a control. The levels of STATS activation (%) are shown for NK cells, CD8+ T cells, effector T cells (Teff), and regulatoiy T ceils (Treg), as determined following incubation with rhIL-2 (FIG, 8A), AK032 (FIG, 8B), AKQ35 (FIG.8C), or AK041 (FIG. 8D). FIGs. 9A-9C show STATS activation (%) in PBMCs treated with the construct AK081 or AK032. The AK081 construct with and without prior exposure to MMP10 was tested. An isotype control as well as ano IL-2 negative control was also tested. The levels of STATS activation (%) are shown for NK cells (FIG. 9A), CD8+ T cells (FIG. 9C), and CD4+ T cells (FIG. 9B).FIGs. 10A-10D show the results from STATS activation studies in PBMCs using constructs AK081 and AK11L as well as controls that included an rhIL-2 and anti-RSV antibody. A no-treatment control was also tested. EC50 (pM) is also shown for the rML-2, AK081, and AK111 treatments.STATS activation (%) is shown for CD4+FoxP3+CD25+ cells (FIG. 10A), CD8+ cells (FIG. J OB), and CD4+FoxP3- CD25- cells (FIG. IOC). FIG. 10» provides EC50 (pM) and fold-change data for the AK081, AK111 constructs, as well as the rhiL-2 control.FIGs. HA-1 ID show die results from STATS activation studies in PBMCs using constructs AK167 and AK168, as well as controls that included an rhlL-2 and anti-RSV antibody . A no-treatment control was also tested. EC50 (pM) is also shown for the rhIL-2, AK167, and AK168 treatments. STATS activation (%) is shown for CD4+FoxP3÷CD25+ cells (FIG. 11 A), CD8+ cells (FIG, 11B), and CD4+FoxP3- CD25- cells (FIG. 11 C). FIG. II» provides EC 50 (pM) and fold-change data for the AK167 and AK 168 constructs, as well as the rhlL-2 control. FIGs. 12A-12D show STATS activation (%) in PBMCs treated with the construct AK165 or AK166, or an isotype control or an EL-2-Fc control, that were (+ MMP10) or were not previously exposed to the MMPiO protease. The key as shown in FIG. 12 A also applies to FIG. 12B, and the key as shown in FIG, 12C also applies to FIG. 12D. STAT5 activation (%) is shown for CD4+FoxP3+ T regidatoiy cells (FIG. 12A), CD4+FoxP3- T helper cells (FIG. 12B), CD8+ cytotoxic T cells (FIG. 12C), and CD56+ NK cells (FIG. 12D).FIGs. 13A-13C show STATS activation (%) in PBMCs treated with the construct AK109 or AK110, or an isot pe control or an IL-2-Fc control, that were (+ MMP10) or were not previously exposed to the MMP10 protease. The key as shown in FIG. 12B also applies to FIG. 13A. STAT5 activation (%) is shown for NK cells (FIG. 13A), CD 8 cells (FIG, 13B), and CD4 cells (FIG. 13C). FIGs. 14A-14D show die results from STATS activation studies in PBMCs using the constructs AK211, AK235, AK253, AK306, AK310, AK314, and AK316, as well as an rhIL-2 control. ST AT 5 activation (%) is shown for CD3+CD4+FoxP3+ cells (FIG, 14A), CD3+CD4+FoxP3- ceils (FIG. 14B), and CD3+CD8+ cells (FIG. 14C). FIG. 14D provides EC50 data for each of the tested constructs as well as the rhlL-2 control FIGs. 1SA-15D show the results from STATS activation studies in PBMCs using the constructs AKQ81, AK167, AK216, AK218, AK219, AK220, and AK223 that have been activated by protease, as well as anrliIL-2 control. STATS activation (%) is shown for CD44FoxP3+CD254- regulatory T cells (FIG. ISA), CD44-FoxP3 -CD25- cells (FIG. 15B), and CD8+ cells (FIG. 15C). FIG. 15D provides EC50 data for each of the tested constructs as well as the rh!L-2 control.FIGs. 16A-16C show STATS activation (%) inPBMCs treated with the construct AK081, AK189, AK190, or AK210, or an anti-RSV control. The key as show n in FIG. 16A also applies to FIGs.l6B and16C. STATS activation (%) is shown for regulator T cells (FIG. 16A), CD4 helper T cells (FIG. 16B), and CDS cells (FIG. 16C).FIGs. 17A-17C show 8TAT5 activation (%) inPBMCs treated with the construct AK167, AK191, AK192, or AK193, or an anti-RSV control. The key as shown in FIG. 17A also applies to FIGs. 17B and 17C. STAT5 activation (%) is shown for regulatory T ceils (FIG. 17A), CD4 helper T cells (FIG. 17B), and CDS cells (FIG. 17C).FIGs. 18A-I8D show-· results from pharmacokinetic studies carried out in tumor-bearing mice using the construct AK032, AK081 , AK111 , AK167, or AK168, or an anti-RSV control. FIG. 18A provides a simplistic depiction of the structure of each of the constructs tested. FIG. 18B shows Fc levels in plasma (gg / niL) by detecting human JgG, FIG. 18C shows Fc-CD 122 levels in plasma (pg / mL) by detecting human CD 122, and FIG. 18D shows Fc-IL2 levels in plasma (pg / mL) by detecting human IL- 2. Prior to the detection step, an anti-human IG was used as the capture antibody.FIGs. 19A-19D show results from pharmacokinetic studies carried out in tumor-bearing mice using the construct AK167, AK191 AK197, AK203, AK2.09, or AK211, or an anti-RSV control. FIG. 19A provides a simplistic depiction of the structure of each of the constructs tested. FIG. I9B shows Fc levels in plasma (pg / mL) by detecting human IgG, FIG. 19C show s Fc-IL2 levels in plasma (pg / 'mL) by detecting human IL-2, and FIG. 191) show's Fc-CD 122 levels in plasma (ug / mL) by detecting human CD 122. Prior to the detection step, an anti-human IG was used as the capture antibody.FIGs. 20A-20L show' results from studies testing the in vivo responses of CD4, CDS, NK, and Treg percentages in spleen, biood, and tumor, using the AK032, AK081, AK111, AK167, or AK168 construct, or an anti-RSV IgG control. For spleen tissue, % CDS cells of CD3 ceils (FIG. 20A), % CD4 of CDS cells (FIG. 20B), % NK cells of CD3- cells (FIG. 20C), % FoxP3 of CD4 cells (FIG. 20D) is shown For blood, % CDS cells of CD3 cells (FIG. 20E), % CD4 of CD 3 cells (FIG. 20F), % NK cells of CD3- cells (FIG, 20G), % FoxP3 of CD4 cells (FIG. 20H) is shown. For tumor tissue, % CD 8 cells of CB3 cells (FIG. 201). % CD4 of CD 3 cells (FIG. 20J), % NK cells of CD3- cells (FIG, 20K), % FoxP3 of CD4 cells (FIG, 20L) is shown.FIGs. 21A-21L show' results from studies testing the in vivo responses of CD4, CDS, NK, and Treg percentages in spleen, blood, and tumor, using the AK167, AK168, AK191, AK197, AK2G3, AK209, or AK211 construct or an anti-RSV IgG control. For spleen tissue, % CDS cells of CD3 cells (FIG. 21 A),% CD4 of CD3 cells (FIG. 21B), % NK cells of CD3- cells (FIG. 21C), % FoxP3 of CD4 cells (FIG. 21D) is shown. For blood, % CD 8 cells of CD3 cells (FIG.21E), % CD4 of CDS cells (FIG. 21F), % NK cells of CD3- cells (FIG.21G), % FoxP3 of CD 4 cells (FIG. 2 Hi) is shown. For tumor tissue, % CDS cells of CD 3 cells (FIG. 211), % CD 4 of CD 3 cells (FIG. 21J), % NK cells of CDS- cells (FIG. 21K), % FoxP3 of CD4 cells (FIG. 21L) is shown.FIGs, 22A-22L show results from studies testing the in vivo responses of CD4, CDS, NK, and Treg percentages in spleen, blood, and tumor, using the AK235, AK191, AK192, AK193, AK210, AK189,AK 190, or AK211 construct, or an anti-RSV IgG control. For spleen tissue, % CDS cells of CD3 cells (FIG. 22 A), % CD4 of CD3 cells (FIG. 22B), % NK cells of CD3- cells (FIG. 22C), % FoxP3 of CD 4 cells (FIG, 22D) is shown. For blood, % CDS cells of CD 3 cells (FIG, 22E), % CD4 of CD3 cells (FIG. 22F), % NK cells of CD3- cells (FIG. 22G), % FoxP3 of CD4 cells (FIG. 22H) is shown. For tumor tissue, % CDS ceils of CD 3 cells (FIG. 221), % CD 4 of CD3 cells (FIG. 22J), % NK cells of CD3- cells (FIG. 22K), %FoxP3 of CD4 cells (FIG. 22L) is shown.FIG s. 23A-23I show results from in vivo T cell activation in spleen, blood, and tumor, using the AK235, AK19L AK192, AK193, AK210, AK189, AK190, or AK211 construct. T cell activation was measured as the mean fluorescence intensity (MFI) of CD25 in CD8+ T cells (FIG. 23A; FIG. 23D; FIG. 23G), CD4+ T cells (FIG. 23B; FIG. 23E; FIG. 2311), or Foxp3+ cells (FIG. 23C; FIG. 23F; FIG. 23Ϊ) in the spleen, blood, and tumor. Statistical analysis was performed using One-way ANOVA as compared to the non-cleavabie AK211 construct.FIGs. 24A-24D show the results from studies testing the in vivo cleavage of the exemplary masked IL-2 polypeptide constructs AK168 (cleavabie peptide sequence: MPYDLYHP) and AK209 (cleavable peptide sequence: VPLSLY; SEQ ID NO: 15). FIG. 24E shows results from a pharmacokinetic study of total plasma IgG concentration (pg / inL) for total levels of the AK 167, AK 168, and AK209 constructs, and for levels of no -cleaved forms of each construct.FIGs. 25 A-25D show results from an in vivo study that assessed vascular leakage using the exemplary masked IL-2 polypeptide construct AK111 or AK168, or the non-masked IL-2 polypeptide construct AK081 or AK167, or an anti-RSV control. FIG.25A shows the percentage (%) of body weight loss, andFIGs. 25B, 25C, and 25D shows the weight in grains of the liver, lung, and spleen, respectively, for each.FIGs. 26A and 26B show results from an in vivo study that assessed vascular leakage as indicated bymeasuring the extent of dye leakage into liver and lung tissue following administration of tire AK08L AK111, AK167, or AK168 construct or an anti-RSV control. The extent of dye leakage into liver (FIG. 26A) and lung (FIG. 26B) was measured based on absorbance at 650run.FIGs. 27A and 27B show results from an in vivo study that assessed vascular leakage as indicated by measuring the extent of mononuclear cell perivascular invasion into the liver and lung tissue following administration of the AK081, AKlll, AK167, or AK168 construct, or an anti-RSV control. The average number of mononuclear cells in the liver (FIG. 27A) and the average number of mononuclear cells in the lung (FIG. 27B) depicted for each.FIGs. 28A and 28B show results from a syngeneic tumor model study that assessed tumor vokune and body weight over the course of treatment with the AK032, AK081, AK111, AK167, or AK 168 construct, or an anti-RSV control. FIG, 28.4 show's data on tumor volume over tire course of treatment, and FIG. 28B shows data on the percentage (%) change in body weight over the course of the treatment.FIGs. 29 A and 29B shows AK471 with I253A FcRn mutation induced robust CDS T cells expansion in the TME while remaining inactive in the periphery. FIGs. 30A-3QC show AK471 has slightly shoster half-life compared to aglyco-hlgGlFIGs. 31A-31 C shows there is no evidence of cleavage or decapitation with AK471 in the plasmaFIG 32 show's exemplary IL-12 construct formats.FIGs. 33A and 33B show exemplary cleavage processes for exemplar)' molecules AK380, AK381 and AK384 (FIG34A), and AK383, AK386, AK434, AK447, AK448, AK446, AK528 and AK529 (FIG34B).FIGs. 34A-34D depict the masking of IL-12 towards IL-12RB1, using SPR analysis that tested the binding of exemplar)' masked IL-12 polypeptide constructs (AK384 and AK386) to rh!L-12RBi-Fc.FIG. 34A depicts the interaction between AK384 and IL-12RB1-Fc, FIG. 34B depicts the interaction between AK386 and IL-12RB1-Fc, and FIG. 34C depicts the interaction between a recombinant human IL-12 (rhIL-12) control and IL-32RB1-Fc. FIG. 34D provides a table summarizing the data obtained for the association constant (ka), dissociation constant (kd), equilibrium dissociation constant (KD), as well as the Chi2value and U-value for each interaction. Due to the shape of the curves, accurate kinetics could not be determined and thus the KD is estimated based on the on-rate. These results demonstrate that theseexemplar}' masked IL-12 polypeptide constructs (AK384 and AK386) did not demonstrate detectable binding to IL-I2RB1-Fc, while the wild-type rhIL-12 control did demonstrate detectable binding.FIGs. 35A-35D depict the masking of IL-12 towards IL-12RB2, using SPR analysis that tested the binding of exemplary masked IL-12 polypeptide constructs ( AK384 and AK386) to rhIL-12RB2-Fc. FIG. 35A depicts the interaction between AK384 and IL-12RB2-Fc, FIG. 35B depicts the interaction between AK386 and IL-12RB2-FC, and FIG. 35C depicts the interaction between a recombinant human IL-12 (rML-12) control and 1L-12RB2-Fc. FIG. 35D provides a table summarizing the data obtained for the association constant (ka), dissociation constant (kd), equilibrium dissociation constant (KD), as well as the Chi2value and II -value for each interaction. Due to the shape of the curves, accurate kinetics could not be determined and thus the KD is estimated based on the on-rate. These results demonstrate that an exemplary masked IL-12 polypeptide constmct (AK386) did demonstrate weak yet detectable binding to TL-12RBl~Fc, while the wild-type rblL-12 control and an exemplary IL-12 polypeptide construct (AK384) did demonstrate detectable binding.FIGs 36-40 show the results from Example 6. FIGs 41-43 show the results from Example 7. FIGs 44- 52E show the results from Example 8.FIGs. 53A-53D and FIGs. 54A-54F show the results of a SDS-PAGE and HEK-Blue IL-2 bioassay using exemplary TL-15 constructs AK904 and AK910 that do not include a peptide substrate, and constructs AK932, AK938, AK930 and AK936 that do include a peptide substrate FIGs 53A-53D shows the SDS- PAGE gel results. FIGs. 54A-54F show the HEK-Blue IL-2 bioassay results.FIGs 55-68 show the results of Example 11. The PK / PD of exemplar}' munnized molecules AK944, AK945, AK947 and control AK948 were analysed in vivo in two tumor models, MB49 and B 16F10.FIGs 69-71B show the results of Example 12. The PK, PD, hema tology and serum chemistry of exemplars' molecules AK667, AK92L AK923 and control AK671 were analysed in cynomolgus monkeys.DETAILED DESCRIPTIONBy using a masking moiety, the systemic side effects of an administered IL-12 cytokine or functional fragment thereof can be reduced by interfering with the binding capability of the IL-12 cytokine or functional fragment thereof to its cognate receptor.Interleukin 12 receptor is a type I cytokine receptor, binding interleukin 12. It consists of beta land beta 2 subunitsBy masking the 1L-12 cytokine or functional fragment thereof using a linker that includes a proteolytically cleavabie peptide, tire binding capability that is interfered with by using the masking moiety can be restored by cleavage of the cleavabie peptide at the tumor microenvironment. Tims, the masked lL-12 cytokines provided herein are engineered to precisely target pharmacological activity to the tumor microenvironment by exploiting one of the hallmarks of cancer, high local concentrations of active protease. This feature of the tumor microenvironment is used to transform a systemically inert molecule into a locally active IL-12 cytokine or functional fragment thereof in the form of an IL-12 cleavage product. Activation of the IL-12 cytokine or functional fragment thereof at the tumor microenvironment significantly reduces systemic toxidties that can be associated with drags that are administered to a subject in active form. Thus, the masked IL-2 cytokines of the invention may be viewed as a pro-drag.Masked IL-12 cytokines described herein have been found to show various advantageous properties. Masked IL-12 cy tokines described anywhere herein have been found to be capable of activating immune cells (proliferation and expansion) upon proteoly tic cleavage, preferentially in the tumor microenvironment and at lower levels in the periphery . Masked IL-12 cy tokines described an where herein have been found to be capable of promoting tumor eradication (i.e. show anti-tumor activity') and inhibition of metastasis upon proteolytic cleavage Masked IL-12 cytokines described anywhere herein have been found to demonstrate advantageous prolonged drug exposure. Masked IL-12 cytokines described herein have been found to demonstrate advantageous stability. Masked IL-12 cytokines described herein have been found to demonstrate advantageous tolerability. Further, masked IL-12 cytokines described herein have been found to demonstrate advantageous potency.1. ‘HETEROMMERIC’ MASKED CYTOKINESProvided herein, in some embodiments, is a masked cytokine comprising a masking moiety in a first polypeptide chain and an IL-12 cytokine or functional fragment thereof in a second polypeptide chain. Such masked cytokines may be referred to as ‘heterodinieric’ masked cytokines. In some embodiments, the masked cytokine comprises a protein heterodimer comprising: a) a first polypeptide cltain comprising a masking moiety' linked to a first half-life extension domain via a first linker; and b) a second polypeptide drain comprising an IL-12 cytokine or functional fragment thereof linked to a second half-life extension domain via a second linker, wherein the first half-life extension domain is associated with the second half-life extension domain, and wherein one of the first linker or the second linker comprises a proteolytically cleavabie peptide.The masking moiety, half-life extension domains, IL-12 cytokine or functional fragment thereof, linkers and type of association between the first half-life extension domain and the second half-life extension domain may be any one of those described herein, and any combination of those described herein. In some embodiments, in the first polypeptide chain, the fust half life extension domain is linked to the amino terminus of the first linker and the carboxy terminus of the first linker is linked to the amino terminus of the masking moiety and, in the second polypeptide chain, the second half life extension domain is linked to the amino terminus of the second linker and the carboxy terminus of the second linker is linked to the amino terminus of the IL-12 cytokine or functional fragment thereof. This is shown schematically below where: the first polypeptide drain comprises:N’ HLi-Ll-MM C’ and the second polypeptide drain comprises:N’ HL2-L2-C C’ where HL1 is the first half life extension domain, LI is the first linker, MM is the masking moiety, HL2 is tire second half life extension domain, L2 is the second linker, and C is tire IL-12 cytokine or functional fragment thereof.1.1 1L-12 CytokinesProvided herein is an IL-12 cytokine or functional fragment thereof for use in a masked cytokine or cleavage product thereof. A cytokine plays a role in cellular signalling, particularly in cells of the immune system. IL-12 is an interleukin, which is a type of cytokine signalling molecule in the immune system that regulates activities of white blood cells.Endogenous IL-12 exists as two distinct molecules IL-12 p40 and IL-12 p35, that dimerize in the cell during biosynthesis.The full sequences of IL-12 p40 and IL-12 p35 are (pro-peptides cleaved off during biosynthesis are shown) in bold):IL-12 p40 subunit:MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGE WLTCDTPEEDGITWTLDQSSEYLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQ KEPKNKTFLRCEAK YSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV RGDNKE YE YS .CQED S AGFA AEESLPIEVMVD AWKLKYEN YTS SFFIRDIIKPDPPKK LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRWTDKTSATVIC RKNASISVRAQDRYYSSSWSEWASVPCS IL-12 p35 subunit:MCPARSLLLVATLVLLDHLSLARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEETDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSTYEDLKMYQVEFKTMNAKLLMDPKRQIFI,DQNMl.AVn>ELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASThe mature forms are as follows:IL-12 p40 subunit: lWELKKDVYW^DWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTnSTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFiRDlIKEDPPKNLQLKPLKNSRQVEVSWEYPDT STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSIL-12 p35 subunit:RNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEETDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVTDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNASThey are expressed as two chains that covalently dimerize during bios nthesis through a disulfide bound between the two subunits: Cysteine C199 of the p40 subunit associates with Cysteine C96 of the p35 subunit.“Functional fragments” of an IL-I2 cytokine comprise a portion of a Mi length cy tokine protein which retains or has modified cytokine receptor binding capability (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity' compared to the full length cytokine protein). Cytokine receptor binding capability' can be shown, for example, by the capability' of a cytokine to bind to the cytokine’s cognate receptor or a component thereof.In some embodiments, the IL-12 cytokine or functional fragment thereof is any naturally occurring interleukin-2 (IL-12) protein or modified variant thereof capable of binding to an interleukin- 12 receptor. in some embodiments, the IL-12 polypeptide or functional fragment thereof comprises an IL-12p40 polypeptide or functional fragment thereof covalently linked to an IL-12p35 polypeptide or functional fragment thereof.The 1L-I2p40 polypeptide or functional fragment thereof may be attached to the first half life extension domain such that the first pol eptide chain comprises:N’ HL1-L1-MM C’ and the second polypeptide chain comprises:N’ HL2-L2-fIL-12p40-lmker-IL-12p351 C’where ‘IL-12p40’ is the IL-12p4G polypeptide or functional fragment thereof and TL-12p35’ is the IL- 12p35 polypeptide or functional fragment thereof.In some embodiments, the IL-12p40 polypeptide comprises SEQ ID NO: 1. In some embodiments, the IL- 12p40 polypeptide comprises an amino acid sequence having at least one amino acid modification as compared to the amino acid sequence of SEQ ID NO: 1. Each of the at least one amino acid modifications can be any amino acid modification, such as a substitution, insertion or deletion. In some embodiments, the 1L-12 cytokine or functional fragment thereof comprises an amino acid sequence having 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 at least 10 amino acid substitutions as compared to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the 1L-12 cytokine or functional fragment thereof comprises an amino acid sequence having at least 5 amino acid substitutions as compared to the amino acid sequence of SEQ ID NO: 1.The IL-12p40 polypeptide comprises a glycosaminoglycan (GAG)-binding domain. GAGs, such as heparin and heparan sulphate, have been shown to bind numerous growth factors and cytokines, including IL-12. The physiological significance of tills binding is two-fold. First, GAGs can serve as co-receptors on cell surfaces to maintain high, local concentrations of cytokines. Second, GAGs can regulate bioactivities of growth factors and cytokines through multiple mechanisms including dimerization and protection from proteoly tic degradation.The GAG-binding domain in the mature form of the IL-12 p40 subunit is shown below in hold:IWEUGG3VYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTUTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIW8TDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERV RGDNKEYEYS\ ECQEDSACPAAEESLPIEVMYDAVHKLKYENYTSSFTTRDnKPDPPKN LQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC RKN ASIS VRAQDR YYS88WSEWAS VPCSModifications to the GAG-binding domain (KSKREKKDRY) has been shown herein to increase the PK profile of constructs comprising an IL-12 cytokine with a mutated GAG-binding domain, without any decrease in cytokine activity. Thus, in some embodiments, the IL-12p40 polypeptide comprises at least one amino acid modification to the GAG-binding domain. In some embodiments, the modification to the GAG- binding domain is a deletion mutation. In some embodiments, the modification to the GAG-bindi ng domain is a deletion mutation and at least one substitution mutation in some embodiments, the GAG-binding domain comprises the amino acid sequence KDNTERV. In some embodiments, the IL-12p40 polypeptide comprises the amino acid sequence SEQ ID NO: 57. In someembodiments, the GAG-binding domain comprises the amino acid sequence KDNTEGRV. In some embodiments, the IL-12p40 polypeptide comprises lhe amino acid sequence SEQ ID NO: 58.In some embodiments, the G AG-binding domain consists of the amino acid sequence KDNTERV. In some embodiments, the IL-12p40 polypeptide comprises the amino acid sequence SEQ ID NO: 57. In some embodiments, the GAG-hinding domain consists of the ainino acid sequence KDNTEGRV. in some embodiments, the IL-12p40 polypeptide comprises the amino acid sequence SEQ ID NO: 58.In some embodiments, the IL-I2p40 polypeptide comprises an amino acid sequence having one or more cysteine substitutions as compared to the amino acid sequence of SEQ ID NO: 1 . In some embodiments, the JL-12p40 polypeptide comprises an amino acid sequence Slaving an amino acid substitution at position C252 as compared to the amino acid sequence of SEQ ID NO: S. In some embodiments, the amino acid substitution at position C252 is C252S. In some embodiments, the IL-I2p40 polypeptide comprises an amino acid sequence of SEQ ID NO: 59. In some embodiments, the IL-12p40 polypeptide comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to die amino acid sequence of SEQ ID NO: 59. in some embodiments, the XL-12p40 polypeptide consists of an amino acid sequence of SEQ ID NO: 59. in some embodiments, the IL-12p40 polypeptide comprises an amino acid sequence having one or more cysteine substitutions as compared to the amino acid sequence of SEQ ID NO: 1 , and at least one amino acid modification to the GAG-bi tiding domain. In some embodiments, the IL-12p40 polypeptide comprises an amino acid substitution at position C252S as compared to the amino acid sequence of SEQ ID NO: 1, and the GAG-binding domain comprises tire amino acid sequence KDNTERV. In some embodiments, the IL-12p40 polypeptide comprises an amino acid substitution at position C252S as compared to the amino acid sequence of SEQ ID NO: 1, and the GAG-binding domain comprises the amino acid sequence KDNTEGRV. In some embodiments, the IL-12p40 polypeptide comprises an amino acid sequence of SEQ ID NO: 60. In some embodiments, the IL-I2p40 polypeptide comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 933% 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 60. In some embodiments, the IL-12p40 polypeptide consists of an amino acid sequence of SEQ ID NO: 60.In some embodiments, the IL-12p35 polypeptide comprises SEQ ID NO: 2. In some embodiments, the IL- 12p35 polypeptide comprises an amino acid sequence having at least one amino acid modification as compared to the amino acid sequence of SEQ ID NO: 2. Each of the at least one amino acid modifications can be any amino acid modification, such as a substitution, insertion, or deletion. In some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, ai least 8, ai least 9, or at leasi 10 amino acid substitutions as compared to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the II, -12cytokine or functional fragment thereof comprises an amino acid sequence having at least 5 amino acid substitutions as compared to the amino acid sequence of SEQ ID NO: 2.In some embodiments, the 1L-I2p40 - 1L-I2p35 linker is between 5 and 20 amino acids in length. in some embodiments, the 1L-I2p40 - IL-12p35 linker is rich in amino acid residues G and S. in some embodiments, the TL-12p40 - TL-12p35 linker only includes amino acid residue types selected from the group consisting of G and S.In some embodiments, the IL-I2p40 -- IL-12p35 linker includes [(G)nS], where n=4 or 5.In some embodiments, the IL-I2p40 -- IL-12p35 linker includes a (GGGG8) repeat.In some embodiments, IL-12p4G IL-12p35 linker comprises SEQ ID NO: 3. (GGGGSGGGGSGGGGS)In some embodiments, the IL-12 cy tokine or functional fragment thereof comprises SEQ ID NO: 4 In some embodiments, the IL-12 cy tokine or functional fragment thereof comprises an amino acid sequence having at least one amino acid modification as compared to the amino acid sequences of SEQ ID NO: 1 and 2, Each of the at least one amino acid modifications can be any amino acid modification, such as a substitution, insertion, or deletion. In some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having 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 at least 10 amino acid substitutions as compared to the amino acid sequences of SEQ ID NO: 1 and 2. In some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having at least 5 amino acid substitutions as compared to the amino acid sequences of SEQ ID NO: 1 and 2.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4. in some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 4.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 6L In some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence havi ng about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 61.in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 1%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ IDNO: 62.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 63. In some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 63.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64. in some embodiments, the IL-12 cytokine or functional fragment thereof comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the ammo acid sequence of SEQ ID NO: 64. 1,2 Masking MoietiesProvided herein is a masking moiety for use in a masked cytokine It will be understood that the masking moiety is cleaved from the masked cytokine to form tire cleavage product thereof. The masking moiety masks the IL-12 cytokine or functional fragment thereof in the masked cytokine thereby reducing or preventing binding of tire IL -cytokine or functional fragment thereof to its cognate receptor.The IL-12 receptor, beta 1 , or!L-12R[il is a subunit of the IL-12 receptor complex. IL-12R.pl is also known as CD232 This protein binds to interleukin-12 (IL-12) with a low affinity. This protein forms a disulfide- linked oligomer, which is required for its IL-12 binding activity. The IL-12 receptor, beta 2, or IL- 12Rp2 is a subunit of the EL-12 receptor complex. The coexpression of IL-12Rp i and IL-12Rp2 protein lias been shown to lead to the formation of high-affinity IL-12 binding sites.Methods for determining the extent of binding of a protein (e.g., cytokine) to a cognate protein (e.g., cytokine receptor) are well known in the art.In some embodiments, the masking moiety7comprises an extracellular domain of an IL-12 cytokine receptor, or a subunit or functional fragment thereof.Interleukin- 12 receptor subunit beta-1, also called CD212 has the sequence: MESYlNTWWVmEUElAJSRQGAA.CRTSECCFODPPYPDADSGSASGPRDLRCYRlSSDRY ECSWOYEGPTAGVSHFLRCCLSSGRCCYFAA GSA TRWFSDOAGVSVLYTVTL WVESWAR NQTEKSPEIGLOLYNSVKYEPPLGDIKVSKLAGOLRMEWETPDNOVGAEVQFRHRTPSSPWKLGDCGPODDDTESCLCPLFAJNVAOEFOLRRROLGSOGSSWSKWSSPVCVPPENPPOPO FSVEOLGODGRKRLTLKEOPTOLELPEGCOGLAPGTEATYRLOLHMLSCPCKAKATRTLHLGKMPYLSGAAYFYAVISSNOFGPGLNOJWHIPADTHTEPVALmSVGTNGTTMYWPARA OSMTYCIEWOPVGODGGIA TCSUPAPOPPPPA GMA TYSWSRESGAMGOEKCYYFPiFA SAHPEKLTLWSTVLSTYHFGGNASAAGTPHHVSVKNHSLDSVSVDWAPSLLSTCPGVLKEYVVRCRDEDSKO VSEIFP V OPTETO VPLSGLRA G VA YTVO VRADTA WLRG VWSOPORFSIEInterleukin- 12 receptor subunit beta-2 lias the sequence:MAETFRGCShAFMFmSVLUKAKIDACKRGDVTVKPSHVILLGST!^ITCSLKPROGCFHYSRKNKLILYKFDRRlNFimGHSLNSOVTGLPLGTTLFVCKLACINSDElOlCGAEIFVGVAPEOPONLSCIOKGEOGTVACTWERGRDTHLYTEYTLOLSGPKNLTWOKOCKDIYCDYLDFGINLTPESPESNFTAKVTAWSLGSSSSLPSTFTFLDIVRPLPPWDIRIKFOKASVSRCTLYiVRDEGL VLIJ RLRYRPSNSRLWNMVNVTKAKGRHDLLDLKPFTEYEFOISSKLHLYKGSWSDWSESLRAOTPEEEPTGKiLDVWYMKRIUDYSROOISLFWKNLSVSEARGKILHYLLAPROVSANSEGMDNiLVTWOPPRKDPSAVQEYWEWRELHPGGDTOVPLNfVLRSRPYNVSAUSENIKSYICYEIRVYALSGDOGGCSSlLGNSKIfKAPLSGPHlNAlTEEKGSILISWNSIPVOEOMGCLLHYRlYWKERDSNSOPOLCEIPYRVSONSHPINSLOPRVrYVLWMTALTAAGESSHGNEREFCLOGKAm'MAFf'APSICIAIJMl^GIFSTBYFOOKWViA.AAIMVOWCSREIPDPANSTCAKKYPIAEEKTOLPLDRLLIDWPTPEDPEPLVISEVLHOVTPVFRHPPCSNWPOREKGIOGHOASEKP3MMHSASSPPPPRALOAESROLVDLYKVLESRGSPPKPENPACPWTVLPAGDLPTHDGYLPSNIDDLPSHEAPLADSLEELEPOHIST.SVFPSSST.HPT,TFSCGDKLTLDOLKMRCDSLMLThe bold indicates the pro-peptide, the italics with underline indicates the extracellular domain, the italics indicates the transmembrane domain and the bold with underline indicates the cytoplasmic domain. in some embodiments, the masking moiety comprises the extracellular domain of human TL-12R[il or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to !L-12. In some embodiments, the masking moiety comprises art amino acid sequence having an amino acid sequence of human lL-12Rpl with one to four amino acid substitutions. In some embodiments, the masking moiety comprises art amino acid sequence having an amino acid sequence of human IL-12RJ31 with one or two amino acid substitutions.in some embodiments, the masking moiety comprises residues 24 to 237 of human IL-12Rpi, namely a sequence having SEQ ID NO: 5 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to EL- 12. In some embodiments, the masking moiety comprises IL-12Rpi having SEQ ID NO: 5. In some embodiments, the masking moiety comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 5. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 5 with one to four amino add substitutions. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ TD NO: 5 with one or two amino acid substitutions.In some embodiments, the masking moiety comprises residues 24 to 545 of human TL-12R[31, namely a sequence having SEQ ID NO: 6 or a fragment portion, or variant thereof that retains or otherwise demonstrates an affinity to II, -12. In some embodiments, the masking moiety comprises IL-12R[31 having SEQ ID NO: 6. In some embodiments, the masking moiety comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 6 with one to four amino acid substitutions In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 6 with one or two amino acid substitutions.In some embodiments, the masking moiety comprises the extracellular domain of human TL-12R[32 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12. In some embodiments, the masking moiety comprises an amino acid sequence having an amino acid sequence of human IL-12Ri32 with one to four amino acid substitutions In some embodiments, the masking moiety comprises an amino acid sequence having an amino acid sequence of human 1L-12R[32 with one or two amino acid substitutions.In some embodiments, the masking moiety comprises residues 24 to 212 of human IL-12R 2, namely a sequence having SEQ ID NO: 7. In some embodiments, the masking moiety comprises an amino acid sequence laving about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 7 with one to four amino acid substitutions. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 7 with one or two amino acid substitutions.In some embodiments, the masking moiety comprises residues 24 to 222 of human TL-12R[32, namely a sequence having SEQ ID NO: 8. In some embodiments, the masking moiety comprises an amino acidsequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 8 with one to four amino acid substitutions. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 8 with one or two amino acid substitutions.In some embodiments, the masking moiety comprises residues 24 to 319 of human TL-12R(32, namely a sequence having SEQ ID NO: 9. In some embodiments, the masking moiety comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 9. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 9 with one to four amino acid substitutions. In some embodiments, the masking moiety comprises an amino acid seqitence having the amino acid sequence of SEQ ID NO: 9 with one or two amino acid substitutions. in some embodiments, the masking moiety comprises residues 24 to 319 of human 1L-12R[32, namely a sequence having SEQ ID NO: 9, with one or more cysteine substitutions In some embodiments, the masking moiety comprises residues 24 to 319 of human IL-12R[32, namely a sequence having SEQ ID NO: 9, with an amino acid substitution at position C242. In some embodiments, the amino acid substitution is at position C242 is C242S. In some embodiments, the masking moiety comprises an amino acid sequence of SEQ ID NO: 65. In some embodiments, the masking moiety comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 65 In some embodiments, the masking moiety consists of an amino acid sequence of SEQ ID NO: 65 In some embodiments, the masking moiety comprises residues 24 to 622 of human IL-12Rp2, namely a sequence having SEQ ID NO: 10. In some embodiments, the masking moiety comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 10. In some embodiments, the masking moiety comprises an amino acid sequence laving the amino add sequence of SEQ ID NO: 10 with one to four amino acid substitutions. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 10 with one or two ammo acid substitutions.In some embodiments, the masking moiety comprises residues 24 to 227 of human 1L-12 (32, namely a sequence having SEQ ID NO: 11. In some embodiments, the masking moiety comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of SEQ ID NO: 11. In some embodiments. She masking moiet comprises an amino acid sequence having the amino acid sequenceof SEQ ID NO: 11 with one to four amino acid substitutions. In some embodiments, the masking moiety comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 11 with one or two amino acid substitutions. 1.3 LinkersProvided herein are linkers for use in a masked cytokine or cleavage product thereof. A linker as provided herein refers to a peptide of two more amino acids that is used to link two functional components together in the masked cytokines described herein.The masked cytokine comprises a first linker and a second linker, where one of the first linker or the second linker comprises a proteoiyticaliy cieavable peptide.In some embodiments, the second linker comprises a proteoiyticaliy cieavable peptide (linker herein referred to as a ‘proteoiyticaliy cieavable linker’) and the first linker does not comprise a proteoiyticaliy cieavable peptide (linker herein referred to as a non-pro teolytically cieavable linker’) such that the first polypeptide chain comprises;N’ HLl-non-deavable LI -MM C and the second polypeptide chain comprises N’ HL2-deavab!e L2-C C’In some embodiments, the first linker comprises a proteoiyticaliy cieavable peptide (linker herein referred to as a ‘proteoiyticaliy cieavable linker’ or ‘cieavable linker5) and the second linker does not comprise a proteoiy ticaliy cieavable peptide (linker herein referred to as a ‘noii-proteolyticaily cieavable linker’ or ‘non-cleavable linker’) such that the first polypeptide drain comprises:N’ HLl- cieavable LI -MM C’ and the second polypeptide chain comprisesN’ HL2- non-cleavable L2-C C’ The non-cleavable Sinkers and cieavable linkers of some embodiments are described in more detail below.1.3.1 Non-Proteolytically Cieavable Linkers in some embodiments, tire non-cleavable linker is between 3 and 18 amino acids in length. in some embodiments, the non-cleavable linker is between 3 and 15 amino acids in length.in some embodiments, the non-cleavable linker is rich in amino acid residues G and S. in some embodiments, the non-cleavable linker only includes amino acid residue types selected from the group consisting of G and S. in some embodiments, the non-cleavable linker includes [(G)nS j, where n=4 or 5. in some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 12 (GGGGS).In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SF.Q ID NO: 13 (GGGGSGGGGS)In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 14 (GGSGGGSGGGGGS). in some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 54 (GGSGGSGGSGGSGGSSGP) in some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 55 (PGGSGP). in some embodiments, the non-cleavable Sinker comprises an amino acid sequence as shown in SEQ ID NO: 56 (GGSPG)In some embodiments, wherein the second linker comprises a proteoly ticaliy cieavable peptide such that the second linker is a proteoly ticaliy cieavable linker and the first {inker does not comprise a proteoly ticaliy cieavable peptide such that the first linker is a non- proteolytically cieavable linker, the non-cleavable linker is between 3 and 18 amino acids in length. In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 12 (GGGGS) In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 13 (GGGGSGGGGS). In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 14 (GG SGGGSGGGGGS). In some embodiments, the non-cleavable linker comprises an amino acid sequence as show'll in SEQ ID NO: 54 (GGSGGSGGSGGSGGSSGP). In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 55 (PGGSGP). In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 56 (GGSPG).in some embodiments, it is desirable for the first and second polypeptide chains to be of the same or a similar length to facilitate the first half life extension domain associating with the second half life extension domain and the masking moiety masking the IL.-12 cy tokine or functional fragment thereof in the assembled construct. As such where the masking moiety is a shorter amino acid sequence than the IL-12 cytokine or functional fragment thereof, the difference in length may be compensated fully or in part by using a longer linker LI.1.3.2 Proteolytically Cleavable Linkers In some embodiments, the cleavable linker is from 10 to 25 amino acids in length.In some embodiments, the cleavable linker comprises a proteolytically cleavable peptide (CP) flanked on both sides by a spacer domain (SD) as shown below:SD-CP-SDCleavable PeptidesThe cleavable linker comprises a cleavable peptide. A cleavable peptide is a polypeptide that includes a protease cleavage site, such that the cleavable peptide is proteolytically cleavable. Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins A “cleavage site” as used herein refers to a recognizable site for cleavage of a portion of the cleavable peptide found in any of the linkers that comprise a cleavable peptide described herein. Thus, a cleavage site may be found in the sequence of a cleavable peptide as described herein. In some embodiments, the cleavage site is an amino acid sequence that is recognized and cleaved by a cleaving agent.In some embodiments, the protease cleavage site is a tumor-associated protease cleavage site. A “tumor- associated protease cleavage site” as provided herein is an amino acid sequence recognized by a protease whose expression is specific or upregulated for a tumor cell or tumor cell environment thereof.The tumor cell environment is complex and can comprise multiple different proteases. As such, lire precise site at which a given cleavable peptide will be cleaved in the tumor ceil environment may vary between tumor types, between patients with the same tumor type and even between cleavage products formed in the same tumor dependent on the specific tumor cell environment. Moreover, even after cleavage, further modification of the initial cleavage product, e.g. by removal of one or two terminal amino acids, may occur by the further action of proteases in the tumor cell environment. A distribution of cleavage products canthus be expected to form in the tumor cell environment of a patient following administration of a single structure of a masked cytokine as described herein.It will be understood that a cleavage site as referred to herein refers to a site between tw o specific ainino acid residues within the cleavable peptide that are a target for a protease known to be associated with a tumor cell environment. In this sense, there may be more than one cleavage site present in a cleavable peptide as described herein where different proteases cleave the cleavable peptide at different cleavage sites. It is also possible that more than one protease may act on the same cleavage site within a cleavable peptide. Discussion of protease cleavage sites can be found in the art.Thus, the cleavable peptides disclosed herein may be cleaved by one or more proteases.In some embodiments, the cleavable peptide is a substrate for a protease that is co-localized in a region or a hssue expressing the IL-12 cytokine receptor.In some embodiments, the cleavable peptide is a 5-rner (i.e. peptide 5 amino acids in length), 6-mer (i.e. peptide 6 amino acids in length), 7-rner (i.e. peptide 7 amino acids in length), 8-mer (i.e. peptide 8 amino acids in length), 9-mer (i.e. peptide 9 amino acids in length), 10-mer (i.e peptide 10 amino acids in length), 11-mer (i.e. peptide II amino acids in length), 12-mer (i.e. peptide 12 amino acids in length), 13-mer (i.e. peptide 13 amino acids in length), 14-tner (i.e. peptide 14 amino acids in length), 15-mer (i.e. peptide 15 amino acids in length), 16-mer (i.e. peptide 16 amino acids in length), 17- mer (i.e. peptide 17 amino acids in length), or 18-mer (i.e. peptide 18 amino acids in length).In some embodiments, the cleavable peptide is from 5 to 18 amino acids in length. In some embodiments, the cleavable peptide is from 6 to 10 amino acids in length. in some embodiments, the cleavable peptide within the cleavable linker comprises an amino acid sequence selected from the group consisting of:Purely by way of example, in the above table, * indicates a known or observed protease cleavage site within the cieavable peptide. in some embodiments, the cieavable peptide comprises an ammo acid sequence of SEQ ID NO: 15. (VELS*LY), for example the cieavable peptide may comprise an amino acid sequence of SEQ ID NO: 210 (VPLSLYSG). in some embodiments, the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 41. (MPYD*LYHP). In some embodiments, the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 42. (DSGG*FMLT). In some embodiments, the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 43. (RAAA*VKSP). In some embodiments, the cieavable peptide comprises an amino add sequence of SEQ ID NO: 44. (ISSGLL*SGRS), for example tire cieavable peptide may comprise an amino acid sequence of SEQ ID NO: 21 1 (ISSGLLSGRSDQP). In some embodiments, the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 45. (DLLA* VVAAS). in some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 15. (VPLS*LY). in some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 210 (VPLSLYSG). In some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 41. (MPYD*LYHP). In some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 42. (DSGG*FMLT). In some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 43 (RAAA*VKSP). In some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 44. (ISSGLL*SGRS). in some embodiments, the cieavable peptide consists of an amino add sequence of SEQ ID NO: 211 (ISSGLLSGRSDQP). In some embodiments, the cieavable peptide consists of an amino acid sequence of SEQ ID NO: 45. (DLLA*WAAS).Cieavable peptides having an amino add sequence as shown in SEQ ID NOs: 44 or 45 have been found to demonstrate very specific cleavage in the tumor cell environment compared to non-tumor celi environment. Thus, when these cieavable peptides are incorporated into a masked IL-I2 cytokine as disclosed any here herein, any s stemic side effects of the administered IL-12 cytokine or functional fragment thereof may be further reduced.Spacer DomainsA spacer domain may consist of one or more amino acids. The function of the spacer domains, where present, is to link the prateo!yticaliy cieavable peptide (CP) to the other functional components in the constructs described herein.it will be understood that spacer domains do not alter the biological interaction of the proteolytically cleavable peptide with proteases in the tumor-cell environment or in non-tumor cell environment. In other- words, even in the presence of spacer domains lire inventive proteolytically cleavable peptides disclosed herein retain their advantageous tumor specificity.In some embodiments, the spacer domains flanking the proteolytically cleavable peptide are different.In some embodiments, the spacer domains are rich in amino acid residues G, S and P. In some embodiments, the spacer domains only includes amino add residue types selected from the group consisting of G, S and P.In some embodiments, the cleavable linker comprises:N’ SD1-CP-8D2 C' where SDi is a first spacer domain and SD2 is a second spacer domain, in some embodiments, tire cleavable linker comprises:N’ SD1-CP-SD2 C’ in some embodiments, the first polypeptide chain comprises:N’ HLl-non-cleavable LI -MM C’ and the second polypeptide chain comprises:N’ HL2- SD1-CP-SD2 ~C C' In some embodiments, tire first polypeptide chain comprises:N’ HL1- SD1-CP-SD2 -MM C’ and the second polypeptide chain comprises:N’ Hi.2- non-cleavable L2-C C’ in some embodiments, the N-termirius of SD1 is a glycine (G).In some embodiments, the first spacer domain (SD1) is between 3 and 10 amino acids in length. In some embodiments, the first spacer domain (SDi) is between 5 and 9 amino acids in length. In some embodiments, SDI comprises SEQ ID NO: 16. (GGSGGS)In some embodiments, SDI comprises SEQ ID NO: 17. (GG8GGSGG8)in some embodiments, the C-termimis sequence of SD2 is -GP C’.In some embodiments, the second spacer domain (SD2) is between 3 and 6 amino acids in length. In some embodiments, SD2 comprises SEQ ID NO: 18. (SGP)Exemplars' combinations of SD1 and SD2 in a cleavable linker are shown below:In some embodiments, the proteolytical!y cleavable linker comprises SD1-CP-SD2 where SD1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP has an amino acid sequence as shown in SEQ ID NO: 44. In some embodiments, the spacer domains are rich in amino acid residues G, S and P. In some embodiments, the spacer domains only include amino acid residue types selected from the group consisting of G, S and P. In some embodiments, tire proteolytically cleavable linker comprises SD1-CP-SD2 where SD1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP lias an amino acid sequence as shown in SEQ ID NO: 45. In some embodiments, the spacer domains are rich in amino acid residues G, S and P. In some embodiments, the spacer domains only include amino acid residue types selected from the group consisting of G, S and P. in some embodiments, the proteolytically cleavable linker comprises SD1-CP-SD2 where SD1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP has an amino acid sequence as shown in SEQ ID NO: 44 and SD2 Iras an amino acid sequence as shown in SEQ ID NO: 18. In some embodiments, tire SD1 is from 3 to 6 amino acids in length. In some embodiments, the spacer domains me rich in amino acid residues G, S and P. In some embodiments, the spacer domains only include amino acid residue types selected from the group consisting of G, S turd P.In some embodiments, the proteolytically cleavable linker comprises SD1-CP-SD2 where SD1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP has an amino acid sequence as shown in SEQ ID NO: 45 and SD2 has an amino acid sequence as shown in SEQ ID NO: 18. In some embodiments, the SD1 is from 3 to 6 amino adds in length. In some embodiments, wherein the spacer domains are rich in amino acid residues G, S and P. in some embodiments, the spacer domains only include amino acid residue types selected from the group consisting of G, S and P. In some embodiments, the cleavable linker comprises SEQ ID NO: 19. (GGSGGSVPLSLYSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 20. (GGSGGSGGSVPLSLYSGP)In some embodiments, tire cleavable linker comprises SEQ ID NO: 46. (GGSGGSMPYDLYHPSGP) in some embodiments, lire cleavable linker comprises SEQ ID NO: 47. (GGSGGSGGSMPYDLYHPSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 48. (GGSGGSDSGGFMLTSGP) in some embodiments, the cleavable linker comprises SEQ ID NO: 49 (GGSGGSGGSDSGGFMLTSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 50. (GGSGGSRAAAVKSPSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 51. (GGSGGSGGSRAAAVKSPSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 52. (GGSGGSISSGLLSGRSSGP)In some embodiments, the cleavable linker comprises SEQ ID NO: 53. (GGSGGSGGSISSGLLSGRSSGP).In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 12 (GGGGS) and the cleavable linker comprises SEQ ID NO: 19 (GGSGGSVPLSLYSGP).In some embodi ents, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 13 (GGGGSGGGGS) and the cleavable linker comprises SEQ ID NO: 19 (GGSGGSVPLSLYSGP).In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 14 (GGSGGGSGGGGGS) and the cleavable linker comprises SEQ ID NO: 19 (GGSGGSVPLSLYSGP).In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 12 (GGGGS) and the cleavable linker comprises SEQ ID NO: 20 (GGSGGSGGSVPLSLYSGP).In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID INO: 13 (GGGGSGGGGS) and the cleavable linker comprises SEQ ID NO: 20 (GGSGGSGGSVPLSLYSGP). In some embodiments, the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 14 (GGSGGGSGGGGGS) and the cleavable linker comprises SEQ ID NO: 20 (GGSGGSGGSVPLSLYSGP),In some embodiments, wherein the second linker comprises a proteolyticaUy deavab!e peptide such that the second linker is a proteolyticaUy cleavable linker and the first linker does not comprise a proleolylically cleavable peptide such that the first linker is a non- proteolyticaUy cleavable linker, the cleavable linker comprises SEQ ID NO: 46 and the non-cleavable li nker comprises SEQ ID NO: 55 In some embodiments, the cleavable linker comprises SEQ ID NO: 47 and the non-cleavable linker comprises SEQ ID NO: 55. In some embodiments, the cleavable linker comprises SEQ ID NO: 48 and die non-cleavable linker comprises SEQ ID NO: 55. In some embodiments, the cleavable linker comprises SEQ ID NO: 49 and the non- cleavable linker comprises SEQ ID NO: 56. In some embodiments, the cleavable linker comprises SEQ ID NO: 50 and the non-cleavable linker comprises SEQ K) NO: 55. In some embodiments, the cleavable linker comprises SEQ ID NO: 50 and the non-cleavable linker comprises SEQ ID NO: 14. In some embodiments, the cleavable linker comprises SEQ ID NO: 51 and the non-cleavable linker comprises SEQ ID NO: 56. In some embodiments, the cleavable linker comprises SEQ ID NO: 51 and the non-cleavable linker comprises SEQ ID NO: 14. In some embodiments, the cleavable linker comprises SEQ ID NO: 52 and the non- cleavable linker comprises SEQ ID NO: 55. In some embodiments, the cleavable linker comprises SEQ ID NO: 52 and the non-cleavable linker comprises SEQ ID NO: 14. In some embodiments, the cleavable linker comprises SEQ ID NO: 53 and the non-cleavable linker comprises SEQ ID NO: 56. In some embodiments, the cleavable linker comprises SEQ ID NO: 53 and the non-cleavable linker comprises SEQ ID NO: 14.In some embodiments, the proteolyticaUy cleavable linker comprises a cleavable peptide consisting of an amino acid sequence of SEQ ID NO: 44 (TSSGLL*SGRS).In some embodiments, the proteolyticaUy cleavable linker comprises a cleavable peptide consisting of an amino acid sequence of SEQ ID NO: 45 (DLLA*VVAAS).Linker combinations disclosed herein and disclosed in exemplary AK molecules may be used with any 1L- 12 cytokine or fragment thereof disclosed herein. Linker combinations disclosed herein and disclosed in exemplary AK molecules may be used with any masking moiety'disclosed herein. Linker combinations disclosed herein and disclosed in exemplary AK molecules may be used with any half-life extension domains. In oilier words, the linkers disclosed in exemplary AK molecules may be used In combinationswith any 1L-12 cytokine or fragment thereof disclosed herein, masking moiety disclosed herein and / or half- life extension domain disclosed herein.1.4 Half-life Extension DomainsProvided herein are half life extension domains for use in a masked cy iokine or cleavage product thereof. A long half-life in vivo is important for therapeutic proteins. Unfortunately, cytokines that are administered to a subject generally have a short half-life since they are normally cleared rapidly from the subject by mechanisms including clearance by the kidney and endocytic degradation. Thus, in the masked cytokine provided herein, a half-life extension domain is (inked lo the masked cytokine for the purpose of extending the half-life of the cytokine in vivo.The term “half-life extension domain”refers to a domain that extends the half-life of the target component in serum. The term “half-life extension domain” encompasses, for example, antibodies and antibody fragments.The masked cytokine provided herein comprises a first half-life extension domain that is associated with a second half-life extension domain. In some embodiments, the first half-life extension domain and the second half-life extension domain are riori-covalentiy associated.In some embodiments, the first half-life extension domain and the second half-life extension domain are covalently bound. in some embodiments, the first half-life extension domain is linked to the second half-life extension domain via one or more disulphide bondsIn some embodiments, the first half-life extension domain is linked to tire second half-life extension domain via a half life extension domain linker (HLDL). in some embodiments, the first half-life extension domain and the second half-life extension domain are non-covalently associated and, further, the first half-life extension domain is linked to the second half-life extension domain via a disulphide bond.In some embodiments, the first half-life extension domain comprises a first antibody or fragment thereof, and second half-life extension domain comprises a second antibody or fragment thereof.An antibody or fragment thereof that is capable of FcRn-mediated recycling, can be reduce or otherwise delay clearance of die masked cy tokine from a subject, thereby prolonging the half-life of the administered masked cytokine. In some embodiments, the antibody or fragment thereof is any antibody or fragment thereof that is capable of FcRn-mediated recycling, such as any heavy chain polypeptide or portion thereof (e.g., Fc domain or fragment thereof) that is capable of FcRn-mediated recycling.The antibody or fragment thereof can be any antibody or fragment thereof However, in some embodiments of a masked cytokine comprising a first half-life extension domain and a second half-life extension domain, either the first half-life extension domain or the second half-life extension domain may comprise an antibody or fragment thereof that does not bind to the FcRn receptor, such as a light chain polypeptide. For example, in some embodiments of the masked cy tokine, a first half-life extension domain comprises an antibody or fragment thereof that comprises a light chain polypeptide or portion thereof that does not directly interact with the FcRn receptor, but the masked cy tokine nonetheless has an extended half-life due to comprising a second half-life extension domain that is capable of interacting with the FcRn receptor, such as by comprising a heavy chain polypeptide. It is recognized in the art that FcRn-mediated recycling requires binding of the FcRn receptor to the Fc region of the antibody or fragment thereof. For instance, studies have shown that residues 1253, S254, H435, and Y436 (numbering according to the KabatEU index numbering system) are important for the interaction between the human Fc region and the human FcRn complex. See, e.g., Firan, M., et al, Int Immunol. 13 (2001) 993-1002; Shields, R.L., et al, J. Biol. (Them. 276 (2001) 6591-6604). Various mutants of residues 248-259, 301-317, 376-382, and 424-437 (numbering according to the Rabat EU index numbering syste ) have also been examined and reported. Yeung, Y. A., et al. (J. Immunol. 182 (2009) 7667-7671.In some embodiments, tire antibody or fragment thereof comprises either a heavy chain polypeptide or a light chain polypeptide. In some embodiments, the antibod or fragment thereof comprises a portion of either a heavy chain polypeptide or a light chain polypeptide. In some embodiments, the antibody or fragment thereof comprises an Fc domain or fragment thereof. In some embodiments, the antibody or fragment thereof comprises a CH2 raid CH3 domain or a fragment thereof. In some embodiments, the antibody or fragment thereof comprises the constant domain of the heavy chain polypeptide. In some embodiments, the antibod or fragment thereof comprises the constant domain of the light chain polypeptide. In some embodiments, the antibody or fragment thereof comprises a heavy chain polypeptide or fragment thereof (e.g., an Fc domain or fragment thereof). In some embodiments, the antibody or fragment thereof comprises a light chain polypeptide.In some embodiments, the first half-life extension domain comprises a first Fc domain or a fragment thereof and the second half-life extension domain comprises a second Fc domain or a fragment thereof.in some embodiments, the first and / or second Fc domains each contain one or more modifications that promote the noii-covaient association of die first and the second half-life extension domains in some embodiments, the first half-life extension domain comprises an IgGl Fc domain or fragment thereof including the mutations Y349C; T366S; L38A; and Y407V to form a‘hole’ in the first half-life extension domain and the second half-life extension domain comprises an IgGl Fc domain or fragment thereof including the mutations S354C and T366W to form the ‘knob’ in the second half-life extension domain.In some embodiments, the first and second half-life extension domains are each an IgGl, IgG2 or TgG4 Fc domain or fragment thereof. In some embodiments, the first and second half-life extension domains are each an IgGl Fc domain or fragment thereof. Human IgGl Immunoglobulin heavy constant gamma 1 lias the sequence:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG P5VFLFPPKPKDTLMiSRTP£VTCW¥DVSHEDPEVKFNW¥VD£SV£VHMAKTKPR£EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPiEKTISitA GQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 21)In some embodiments, the first and second half-life exterrsion domains are derived from the sequence for human IgGl Immunoglobulin heavy constant gamma 1 having SEQ ID NO: 21 (the ‘parent sequence’), such that the first and second half-life extension domains each comprise SEQ ID NO: 21 or fragment thereof, with one or more amino acid modifications. in some embodiments, the first and second half-life extension domains each comprise the portion of SEQ ID NO: 21 shown in bold above, optionally with one or more amino acid modifications, i.e.:DKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSWRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 22) in some embodiments, the first and second half-life extension domains comprise SEQ ID NO: 22 with amino substitutions to promote association of the first and second half-life extension domains according to the ‘knob into holes’ approach. In some embodiments, the sequence SEQ ID NO: 22 contains mutations Y349C; T3668; L38A; and Y407V (numbered according to the Rabat F.U numbering system) to form the ‘hole’ in the first half-life extension domain and mutations S354C and T366W (numbered according to theKabat EU numbering system) to form the ‘knob’ in the second half-life extension domain. These modified sequences have SEQ ID NOs 23 and 24 shown below:First half-life extension domain (Y349C; T366S; L38A; and Y407V) SEQ ID NO 23:DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQ VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSecond half-life extension domain (S354C and T366W) SEQ ID NO 24:DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLT\ / LHQDWLNGKEYKCKVSNKALPAPIEmSKAKGQPREPQVYTLPPCRDELTK NQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG in some embodiments, the first and second half-life extension domains each further comprise amino substitution N297A, numbered according to the Kabat EU numbering system:First half-life extension domain (Y349C; T366S; L38A; Y407V and N297A) SEQ ID NO 25:DKTHTCPPCPAPELLGGPSWLFPPKPKDTLMISRTPEVTCVVVDVSHF. DPEVKFN VDG A / HNAKTKPREEQYASTYRWS\TFTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQ VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKL TVDKSRWQQGNVFSCSVYffiEALHNPIYTQKSLSLSPGSecond half-life extension domain (S354C, T366W and N297A) SEQ ID NO 26:DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWY'VDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAW.WESNGQPENNYKTTPPVLDSDGSFFL YSKIY\T)KSRWQQGN SCSVTvIHE.ALHNHYTQKSLSLSPGin some embodiments, the first and second half-life extension domains each further comprise lire amino substitution 1253 A, numbered according to the Kabat EU numbering sy stem.In some embodiments, the first and second half-life extension domains each further comprise both the amino substitutions N297A and 1253A, numbered according to the Kabat EU numbering system:First half-life extension domain (Y349C; T366S; L38A; Y407V, N297A and I253A) SEQ ID NO 27:DKTHTCPPCPAPELLGGPSWLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP1EKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSecond half-life extension domain (S354C, T366W, N297A and I253A) SEQ ID NO 28:DKTHTCPPCP APELLGGP S VFLFPPKPKDTLMASRTPEVTCVA’VD VSHEDP E VKFN W Y VD GVEVHN AKTKPREEQ Y ASTYR W S VLTVLHQD WLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVESCSVMHEALHNHYTQKSLSLSPGIn some embodiments, the first half-life extension domain comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% seque nce identity to any one of the amino acid seque nce of any one of SEQ ID NOs: 22, 23, 25, and 27In some embodiments, the second half-life extension domain comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the amino acid sequence of any one of SEQ ID NOs: 22, 24, 26 and28In some embodiments, the first half-life extension domain comprises an amino acid sequence having one or more modifications, such as one or more amino acid substitutions, additions, or deletions, as compared to the amino acid sequence of any one of SEQ ID NOs: 22, 23, 25, and 27. In some embodiments, the second half-life extension domain comprises an amino acid sequence having one or more modifications, such as one or more amino acid substitutions, additions, or deletions, as compared to the amino acid sequence of any one of SEQ ID NOs: 22, 24, 26 and 28 The one or more modifications can be anymodifications or alterations described herein, including, in some embodiments, any modifications or alterations disclosed herein that promote heterodimerization of polypeptide chains and / or suppresses homodimerization of polypeptide chains, alter effector function, or enhance effector function in some embodiments, the Fc domain or fragment thereof comprises one or more amino acid substitutions altering effector function in some embodiments, the half-life extension domain is an IgGI Fc domain or fragment thereof and comprises one or more amino acid subs titutions selected from the group consis ting of N297A, N297G, N297Q, L234A, L235A, C220S, C2268, C2298, P238S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, D265A, and P329G, numbered according to the Kabat EU numbering system. In some embodiments, the half-life extension domain is an lgG2 Fc domain or fragment thereof and comprises the amino subsiituiion(s): V234A and G237A; H268Q, V309L, A3305, and A331S; and / or V234A, G237A, P238S, H268A, V309L, and A330S, numbered according to the Kabat EU numbering system. In some embodiments, the half-life extension domain is an IgG2 Fc domain or fragment thereof and comprises one or more amino acid substitutions selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, A33IS, P238S, H268A, and V309L, numbered according to the Kabat EU numbering system. In some embodiments, the half-life extension domain is an IgG4 Fc domain or fragment thereof and comprises the amino suhstitution(s): L235A, G237A, and E318A; S228P, L234A, and L235A; H268Q, V309L, A330S, and P331S; and / or S228P and L235A, numbered according to the Kabat EU numbering system. In some embodiments, the half-life extension domain is an IgG2 Fc domain or fragment thereof and comprises one or more amino acid substitutions selected from the group consisting of L235A, G237A, E318A, S228P, L234A, H268Q. V309L, A330S, and P33IS, numbered according to tire Kabat EU numbering system.In some embodiments, the half-life extension domain comprises Fc domain or fragment thereof that comprises one or more amino acid substitutions enhancing effector function In some embodiments, the half-life extension domain is an IgGI Fc domain or fragment thereof and comprises the amino acid, , , and I332E; K326A and E333A; K326W and E333S; K290E, S298G, and T299A; K290E, S298G, T299A, and K326E; K29QN, S298G, and T299A; K29QN, S298G, T299A, and K326E; K334V: L235S, S239D, and K334V; K334V and Q331M, S239D, F243V, E294L, or S298T; E233L, Q311M, and K334V; L234I, Q 11M, and K334V; K334V and S298T, A330M, or A330F; K334V, Q311M, and either A330M or A33 OF; K334V, S298T, and either A330M or A330F; K334V, S239D, and either A330M or S298T; L234Y, Y296W, andK290Y, F243V, or E294L; Y296W and either L234Y orK290Y; S239D, A330S, and I332E, V264I; F243L and V264I; L328M; I332E; L328M and I332E; V264I and I332E; S239E and I332E; S239Q and I332E; S239E; A330Y; I332D; L328I and I332E; L32.8Q and I332E; V264T; V240I; Y266T; S239D; 8239D and I332D; S239D and I332N; S239D and I332Q: S239E and I332D; S239E and I332N;S239E and I332Q; S239N and I332D; S239N and I332E; S239Q and I332D; A330Y and I332E; V264I, A330Y, and I332E; A330L and I332E; V264I, A330L, and I332E; L234E, L.234Y, or L234I; L235D, L235S, L235Y, orL235I; S239T; V240M; V264Y; A330I; N325T; Ϊ332E and L328D, L328V, L328T, or L3281: V2641, 1332E, and either S239E or S239Q; S239E, V2641, A330Y, and I332E; A330Y, I332E, and either S239D or S239N; A330L, I332E, and either S239D or S239N; V264I, S298A, and 1332E; S298A, 1332E, and either S239D or S239N; S239D, V264I. and I332E; S239D, V264L S298A, and I332E; S239D, V2641, A3 SOL, and 1332E; S239D, 1332E, and A330I; P230A; P230A, E233D, and 1332E; E272Y; K274T, K274E, K274R, K274L, or K274Y; F275W; N276L; Y278T; V302I; E318R; S324D, S324I or S324V; K326T OGK326T; T335D, T335R, orT335Y; V240I and V266I; S239D, A330Y, L332E, andL234I; S239D, A330Y, I332E, and L235D; S239D, A330Y, I332E, and V2401; S239D, A330Y, I332E, and V264T; and / orS239D, A330Y, T332E, and either K326E or K326T, numbered according to the Kabat EU numbering system. In some embodiments, tire half-life extension domain is an IgGl Fc domain or fragment thereof and comprises one or more amino acid substitution(s) selected from tire group consisting of: P230A, E233D, L234E, L234Y, L234I, L235D, L235S, L235Y, L235I, S239D, S239E, S239N, S239Q, S239T, V240I, V24QM, F243L, V264I, V264T, V264Y, V266I, E272Y, K274T, K274E, K274R, K274L, K274Y,F275W, N276L, Y278T, V302L E318R, S324D, S324I, S324V, N325T, K326L K326T, L328M, L328I, L328Q, L328D, L328V, L328T, A330Y, A330L, A3301, I332D, I332E, I332N, 1332Q, T335D, T335R, and T335Y in some embodiments, the half-life extension domain comprises one or more amino acid substitution(s) that enhance binding of the half-life extension domain to FcRn. In some embodiments, the one or more amino acid substitntion(s) increase binding affinity of an Fc-containing polypeptide (e.g., a heavy chain polypeptide or an Fc domain or fragment thereof) to FcRn at acidic pH. in some embodiments, the half- life extension domain comprises one or more amino acid substitution^) selected from the group consisting of M428F; T250Q and M428F; M252Y, S2.54T, and T256E; P257I and N434H; D376V and N434H; P257I and Q3111 ; N434A; N434W; M428F and N434S; V259I and V308F; M252Y, S254T, and T256E; V259I, V308F and M428F; T307Q and N434A; T307Q and N434S; T307Q, E380A, and N434A; V308P and N434A; N434I-I; and V308P. For manufacturing purposes, a signal peptide may be engineered upstream of the half life domain to improve secretion of the protein. The signal peptide is selected according to the cell line’s requirements as is known in the art. it will be understood that tire signal peptide is not expressed as part of the protein that will be purified and formulated as drug product.1.4.1 Heterodimerization ModificationsThe half-life extension domains described herein may include one or more modifications that promote heterodimerization of two different half-life extension domains. In some embodiments, it is desirable topromote heterodimerizaiion of the first and second half-life extension domains such that production of Hie masked cytokine in its correct iieterodimeric form is produced efficiently. As such, one or more amino acid modifications can be made to the first half-life extension domain and one or more amino acid modifications can he made to the second half-life extension domain using any strategy available in the art, including any strategy' as described in Klein et al. (2012), MAbs, 4(6): 653-663. Exemplary strategies and modifications are described in detail below.Knobs-into-Holes ApproachOne strategy for promoting heterodimerization of two different half-life extension domains is an approach termed the “knobs-into-holes”.In some embodiments, the masked cytokine comprises a first half-life extension domain and a second half- life extension domain, each of which comprises a CH3 domain. In some embodiments, the half-life extension domain comprising a CH3 domain is a heavy chain polypeptide or a fragment thereof (e.g., an Fc domain or fragment thereof). The CH3 domains of tire two half-life extension domains can be altered by the “knobs-into-holes” technology, which is described in detail with several examples in, e.g., WO 1996 / 027011; Ridgway, J.B. et al. Protein Eng (1996) 9(7): 617-621; Merchant, A.M., et al, Nat. Biotechnoi. (1998) 16(7): 677-681. See also Klein et al. (2012), MAbs, 4(6): 653-663. Using the knob-into- ho!es method, the interaction surfaces of the two CH3 domains are altered to increase the heterodimerization of the two half-life extension domains containing the two altered CH3 domains. This occurs by introducing a bulky' residue into the CH3 domain of one of the half-life extension domains, which acts as the “knob.” Then, in order to accommodate the bulky residue, a “hole" is formed in the other half- life extension domain that can accommodate the knob. Either of the altered CH3 domains can be the “knob" while the other can be the “hole.” The introductio n of a disulfide bridge further stabilizes the heterodimers (Merchant, A.M., et al, Nat. Biotechnoi (1998) 16(7); Atwell, S., et al, J. Mol Biol. (1997) 270( 1): 26-35) as well as increases yield. it has been reported that heterodimerizaiion yields above 97% can be achieved by introducing the S354C and T366W mutations in a heavy chain lo create the “knob” and by introducing the Y349C, T366S, L368A, and Y407V mutations in a heavy chain to create the “hole” (numbering of the residues according to the Kabat EU numbering system). Carter et al. (2001), J. Immunol. Methods, 248: 7-15; Klein et al. (2012), MAbs, 4(6): 653-663.In some embodiments comprising a first half-life extension domain and a second half-life extension domain, the first half-life extension domain comprises a heavy chain polypeptide or portion thereof (e.g., an Fc domain or fragment thereof) that comprises the amino acid mutations S354C and T366W (numbered according to the Kabat EU numbering system), and the second half-life extension domain comprises aheavy chain polypeptide or portion thereof (e.g., an Fc domain or fragment thereof) that comprises the amino acid mutations Y349C, T366S, L368A, and Y407V (numbered according to the Kabat EU numbering s stem). In some embodiments comprising a first half-life extension domain and a second Mf- hfe extension domain, the first half-life extension domain comprises a heavy chain polypeptide or portion thereof (e.g., an Fc domain or fragment thereof) that comprises the amino acid mutations Y349C, T366S, L368A, and Y407V (numbered according to the Kabat EU numbering system), and tire second half-life extension domain comprises a heavy chain polypeptide or portion thereof (e g., an Fc domain or fragment thereof) that comprises the amino acid mutations 8354C and T366W (numbered according to the Kabat EU numbering system).Additional examples of substitutions that can be made to form knobs and holes include those described in US20140302037A1, the contents of which are herein incorporated by reference. For example, in some embodiments, any of the following amino acid substitutions can be made to a first half-life extension domain (“first domain”) and a paired second half-life extension domain (“second domain”) that each contain an Fc domain: (a) Y407T in the first domain and T366Y in the second domain; (b) Y407A in the first domain and T366W in the second domain; (c) F405A in the first domain and T394W in tire second domain; (d) F405W in the first domain and T3948 in the second domain; (e) Y407T in the first domain and T366Y in the second domain; (f) T366Y and F405A in the first domain and T394W and Y4G7T in the second domain; (g) T366W and F405W in the first domain and T394S and Y407A in the second domain; (h) F405W and Y407A in the first domain and T366W and T394S in the second domain; or (i) T366W in the first domain and T3668, L368A, and Y407V in the second domain, numbered according to the Kabat EU numbering system.In some embodiments, any of the following amino acid substitutions can be made to a first half-life extension domain (“first domain”) and a paired second half-life extension domain (“second domain”) that each contain an Fc domain: (a) Y407T in the second domain and T366Y in the first domain; (b) Y407A in the second domain and T366W in the first domain; (c) F405A in die second domain and T394W in the first domain; (d) F405W in the second domain and T394S in the first domain; (e) Y407T in the second domain and T366Y in the first domain; (f) T366Y and F405A in die second domain and T394W and Y407T in the first domain; (g) T366 W and F405W in the second domain and T394S and Y407A in the first domain; (h) F405W and Y407A in the second domain and T366W and T3948 in the first domain; or (i) T366W in the second domain and T366S, L368A, and Y407V in the first domain, numbered according to the Kabat EU numbering system.In embodiments comprising a first half-life extension domain and a second half-life extension domain that each comprise an Fc domain, any of the heterodimerizing alterations described herein can be used in the Fc domains to promote heteiodimerization of any of the masked cytokines described herein.1.5 Exemplary masked cy tokinesMasked cytokines according to the disclosure can combine a IL-12 cytokine or functional fragment thereof as described anywhere herein; a masking moiety as described anywhere herein; first and second half life domains as described anywhere herein; and cleavable and non-cleavable linkers as described anywhere herein.Furthermore, in an embodiment, any specific sequence disclosed herein may optionally comprise further amino acid substitutions, such as one, two or three substitutions. In another embodiment, sequences having at least 90% homology, preferably 95%, more preferably 99%, to any specific sequence disclosed herein for a domain of the masked cytokines are also encompassed by the invention.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises human IL-12Rpi or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 237 of human IL-12Rpi, namely a sequence having SEQ ID NO: 5 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C: T3668; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, tire masking moiety comprises residues 24 to 545 of human IL-12Rpl, namely a sequence having SEQ ID NO: 6 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises human TL-12R[I2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A),in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 61, the masking moiety comprises human IL-12Rp2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 62, the masking moiety comprises human BL-12Rp2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A)In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 63, the masking moiety comprises human 1E-I2Kb2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the annuo acid sequence of SEQ ID NO: 64, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises human IL-12Rp2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the ammo acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 212 of human !L-12Rp2, namely a sequence having SEQ ID NO: 7, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y4G7V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A)In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 222 of human IL-12Rp2, namely a sequence having SEQ ID NO: 8, and the first half-life extension domain comprises SEQ ID NO: 25(Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 319 of human lL-12Rj)2, namely a sequence having SEQ ID NO: 9, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y4Q7V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 319 of human IL-I2Rp2, namely a sequence having SEQ ID NO: 65, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 63, the masking moiety comprises residues 24 to 319 of human IE-12 b2, namely a sequence having SEQ ID NO: 65, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A: Y4G7V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (8354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12Rp2, namely a sequence having SEQ ID NO: 65, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the masking moiety comprises residues 24 to 319 of human IL-12R$2, namely a sequence having SEQ ID NO: 65, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 622 of human 1L-12R[32, namely a sequence having SEQ ID NO: 10, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A)in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 227 of human IL-12Rp2, namely a sequence having SEQ ID NO: 11, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y4Q7V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises human IL-12R[il or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and 1253 A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 237 of human IL-12R£1, namely a sequence having SEQ ID NO: 5 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407Y, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 545 of human IL-l 2R{31, namely a sequence having SEQ ID NO: 6 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and 1253 A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A)In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises human CE-12Eb2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12 arid the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and 1253 A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety' comprises residues 24 to 212 of human 1L-12R[!2, namely a sequence having SEQ ID NO: 7 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A).in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 222 of human IL-12Rp2, namely a sequence having SEQ ID NO: 8 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C: T366S; L38A; Y407V, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 319 of human 1L-12R{52, namely a sequence having SEQ ID NO: 9 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 622 of human IL-12R$2, namely a sequence having SEQ ID NO: 10 and the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and I253A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 4, the masking moiety comprises residues 24 to 227 of human IL-12R{32, namely a sequence having SEQ ID NO: 11 and tire first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and 1253 A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and I253A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64 and the masking moiety comprises residues 24 to 319 of human IE-1211b2, namely a sequence having SEQ ID NO: 65.In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the ammo acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12R|>2, namely a sequence having SEQ ID NO: 65, the non-cieavahle linker comprises the amino acid sequence of SEQ ID NO: 14, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL- 12Kb2, namely a sequence having SEQ ID NO: 65, the non-cleavable linker comprises the amino acid sequence of SEQID NO: 35, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12R 2, namely a sequence having SEQ ID NO: 65, the non-cieavahle linker comprises the amino acid sequence of SEQ ID NO: 56, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and 297A).In some embodiments, the 11,-32 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL- l 2Kb2, namely a sequence having SEQ ID NO: 65, the cleavable peptide comprises tire amino acid sequence of SEQ ID NO: 41, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and die second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). in some embodiments, the 1L-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12Rp2, namely a sequence hasing SEQ ID NO: 65, the cleavable peptide comprises the amino acid sequence of SEQ ID NO: 43, and the first haSf-Sife extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (8354C, T366W and N297A).In some embodiments, the U .-12. cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12R|32, namely a sequence having SEQ ID NO: 65, the cleavable peptide comprises the amino acid sequence of SEQ ID NO: 44, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In sense embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-l 2 b2, namely a sequence having SEQ ID NO: 65, the cleavable linker comprises the amino acid sequence of SEQ ID NO: 51, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12R|>2, namely a sequence having SEQ ID NO: 65, the cleavable linker comprises the amino acid sequence of SEQ ID NO: 53, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12RP2, namely a sequence having SEQ ID NO: 65, the cleavable linker comprises the amino acid sequence of SEQ ID NO: 46, and the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A)In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12R 2, namely a sequence having SEQ ID NO: 65, the non-cleavable linker comprises the amino acid sequence of SEQ ID NO: 56, the cleavable linker comprises the amino acid sequence of SEQ ID NO: 51, and the first half- life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A). in some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 64, the masking moiety comprises residues 24 to 319 of human 1L-12RP2 namely a sequence having SEQ ID NO: 65, the non-cleavable linker comprises the amino acid sequence of SEQ ID NO: 14, the cleavable linker comprises the amino acid sequence of SEQ ID NO: 53, and the first half- life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W andN297A).In some embodiments, the IL-12 cytokine or functional fragment thereof comprises the amino acid sequence of SEQID NO: 64, the masking moiety comprises residues 24 to 319 of human IL-12Rp2, namely a sequence having SEQ ID NO: 65, the non-cleavable linker comprises the amino acid sequence of SEQ ID NO: 55, the cleavable linker comprises the amino acid sequence of SEQ ID NO: 46, and the first half- life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).In some embodiments of the masked cytokine, the first polypeptide drain comprises:N’ HLl-IJ-MM C’ and the second polypeptide drain comprises:N'HL2-L2- iL-i2p35-lMker-IL-12p40] C’where ‘IL-12p40’ is the IL-12p4G polypeptide or functional fragment thereof and ‘IL-12p35’ is the 3L- 12p35 polypeptide or functional fragment thereof. The first half life extension domain (HL1), the first linker (LI), the masking moiety (MM), the second half life extension domain (HL2), the second linker (L2) and lL-12 cytokine or fragment thereof ([IL-12p35-linker-IL-12p40]) may be as defined anywhere herein.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 34 and a second polypeptide drain comprising an amino acid sequence of SEQ ID NO: 40 In some embodiments, the masked cytokine comprises a first polypeptide drain comprising an amino acid sequence of SF.Q ID NO: 83 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 40In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 34 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 88.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 81 and a second polypeptide chain comprising an antino acid sequence of SEQ ID NO: 88.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 82 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 89. in some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 83 and a second polypeptide chain comprising an amino acid sequence of SEQ 3D NO: 90. in some embodiments, the masked cytokine comprises a first polypeptide chain comprising art a ino acid sequence of SEQ ID NO: 83 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 91.In some embodiments, the masked cytokine comprises a first polypeptide drain comprising an amino acid sequence of SEQ ID NO: 82 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 92in some embodiments, the masked cytokine comprises a first polypeptide chain comprising an a ino acid sequence of SEQ ID NO: 83 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 93. in some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 82 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 94. in some embodiments, the masked cytokine comprises a first polypeptide drain comprising an amino acid sequence of SEQ ID NO: 84 and a second polypeptide chain comprising an amino add sequence of SEQ ID NO: 93In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 84 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 94.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 83 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 95.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 82 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 83 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 97.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 82 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 98.In some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 84 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 97in some embodiments, the masked cytokine comprises a first polypeptide chain comprising an amino acid sequence of SEQ ID NO: 84 and a second polypeptide chain comprising an amino acid sequence of SEQ ID NO: 98. 2, CLEAVAGE PRODUCTProvided herein is a cleavage product of a Tieterodimeric’ masked IL-12 cytokines described hereinThe masked 11,-12 cytokines described herein comprise a cleavabia linker. Upon proteolytic cleavage of the cleavable linker at the cleavage site, a cleavage product comprising the IL-12 cytokine or functional fragment thereof is formed. The IL-12 c tokine or functional fragment thereof in tire cleavage product is activated since it is no longer masked by the masking moiety. The IL-12 cytokine or functional fragment thereof in the cleavage product is therefore capable of binding to the target protein.The tumor cell environment is complex and can comprise multiple different proteases. As such, the precise site at which a given cleavable peptide within a masked IL-12 cytokine will be cleaved in the tumor cell environment may vary between tumor types, between patients with the same tumor type and even between cleavage products formed in the same tumor. Moreover, even after cleavage, further modification of the initial cleavage product, s.g by removal of one or two terminal amino acids, may occur by the further action of proteases in the tumor cell environment. A distribution of cleavage products can thus be expected to form in the tumor cell environment of a patient follo wing administration of a masked cytokine as described herein. Provided herein is a cleavage product capable of binding to IL-12R, die cleavage product comprising an IL-12 cytokine or functional fragment thereof, preparable by proteol tic cleavage of the cleavable peptide in a masked IL-12 cytokine as described anywhere herein.Also provided herein is a cleavage product of a masked IL-12 cytokine, where the cleavage product is capable of binding to IL-12R, the cleavage product comprising an 1L-2 cytokine or functional fragment thereof as defined anywhere herein. Also provided herein is a distribution of cleavage products obtained or obtainable from a single structure of a masked IL- 12 cytokine, where each cleavage product within the distribution of cleavage products (i) is capable of binding to IL-12R and (it) comprises an IL-12 cytokine or functional fragment thereof as defined anywhere herein.Also provided herein is a cleavage product of a masked IL-12 cytokine, where the cleavage product is capable of binding to 1L-I2R, the cleavage product comprising a polypeptide comprising:PCP-SD-C wherein PCP is a portion of a proieolytieaily cleavabie peptide; SD is a spacer domain; and C is i IL- 12 cytokine or functional fragment thereof.Further provided herein is a cleavage product of a masked IL-12 cytokine, where the cleavage product is capable of binding to IL-I2R, the cleavage product comprising a protein heterodimer comprising: a) a first polypeptide chain compri ing a first half-life extension domain; and b) a second polypeptide chain comprising a polypeptide comprising formula 5:HL2-L2-C(5) wherein HL2 is a second half-life extension domain; L2 is a non-cleavable linker; and C is an IL-12 cytokine or functional fragment thereof; and wherein the first half-life extension domain is associated with the second half-life extension domain. Also provided herein is a distribution of cleavage products obtained or obtainable from a single structure of a masked IL-12 cytokine, where each cleavage product within tire distribution of cleavage products (i) is capable of binding to IL-12R and (ii) comprises a protein heterodimer comprising: a) a first polypeptide chain comprising a first half-life extension domain; and b) a second polypeptide chain comprising a polypeptide comprising formula 5:HL2-L2-C(5) wherein HL2 is a second half-life extension domain; L2 is a non-cleavable linker; and C is an IL-12 cytokine or functional fragment thereof; and wherein the first half-life extension domain is associated with the second half-life extension domain.Further provided herein is a cleavage product of a masked IL-12 cytokine, where the cleavage product is capable of binding to IL-S2R, the cleavage product comprising a protein heterodimer comprising: a) a first polypeptide chain comprising a polypeptide comprising:HL1-SD-PCP wherein HL1 is a first half-life extension domain; SD is a spacer domain; arid PCP is a portion of a proieolytieaily cleavabie peptide; and b) a second polypeptide chain comprising a polypeptide comprising:HL2-L2-C wherein HL2 is a second half-life extension domain; L2 is a non-cleavable linker; and C is an IL-12 cytokine or functional fragment thereof; and wherein the first half-life extension domain is associated with the second half-life extension domain.Within the cleavage product, the masking moiety, half-life extension domains, IL-12 cytokine or functional fragment thereof, linkers, space domains and type of association between the first half-life extensiondomain and die second half-life extension domain may be any one of those described herein, and any combination of those described herein.The location of the cleavable peptide determines die structure of the resulting cleavage product comprising the IL-12 cytokine.A “portion of a proteoiy ticaliy cleavable peptide”, refers to a part of die original proteolytically cleavable peptide sequence after cleavage at the cleavage site has occurred. After cleavage, further modification of the initial cleavage product, e.g by removal of one or two terminal amino acids, may also occur by the further action of proteases in the tumor cell environment. As such, cleavage products within the distribution of cleavage products that might be formed in the tumor ceil environment of a patient following administration of a masked cytokine might not contain an portion of the proteolytically cleavable peptide.In some embodiments, a “portion” refers to 1 amino acid, 2 amino acids, 3 amino acids, 4 amino acids, 5 amino acids or 6 amino acids of the original proteoiy ticaliy cleavable peptide sequence. In some embodiments, a “portion” refers to 2 amino acids of the original proteolytically cleavable peptide sequence in some embodiments, a “portion” refers to 3 amino acids of die original proteolytically cleavable peptide sequence in some embodiments, a “portion" refers to 4 amino acids of the original proteolytically cleavable peptide sequence.In some embodiments, the ‘portion’ of the proteolytically cleavable peptide is from 3 to 6 amino acids in length. In some embodiments, the ‘portion’ of the proteolytically cleavable peptide is 3 or 4 amino acids in length. Cleavage sites for cleavable linkers disclosed herein are disclosed below:Purely by way of example, in the above table, * indicates a known or observed protease cleavage site within the deavable peptide.Accordingly, herein disclosed is the cleavage product of any one of the masked cytokines disclosed herein.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 29.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 29.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 66. in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 66. in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 67.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 67. in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 68.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 68.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 69.in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 69. in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 70. in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 70.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 71.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 71.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 72.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 72.In some embodiments, She cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 73. in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 73.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity' to an amino acid sequence selected from the group consisting of SEQ ID NO: 74.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 74.in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85% 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 75. in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 75. in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 76.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 76.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 77.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 77.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 78. in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 78. in some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 79.In some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 79.In some embodiments, the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 80.in some embodiments, the cleavage product comprises an amino acid sequence having an amino acid sequence comprising SEQ ID NO: 80.3. BINDING ASSAYSThe strength, or affinity of immunological binding interactions, such as between a cytokine or functional fragment thereof and a binding partner (e.g., a target protein, such as a cytokine receptor) for which the cytokine or functional fragment thereof is specific, can he expressed in terms of the dissociation constant (Kd) of the interaction, wherein a smaller Kd represents a greater affinity. The binding of the IL-12 cy tokine to the IL-12 cytokine receptor can be expressed in terms of the Kd. In some embodiments, the immunological binding interactions are between a masked cytokine (in tire presence or absence of a protease) and a target protein, such as a cytokine receptor immunological binding properties of proteins can be quantified using methods well known in the art. For example, one method comprises measuring the rates of cytokine receptor (e.g., lL-12R) / cy tokine (e.g., IL-12) complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that equally influence the rate in both directions. Both the “on rate constant” (Kon) and the “off rate constant” (Kofi) can be determined by calculation of the concentrations and the actual rates of association and dissociation. The ratio of KoffiKon enables the cancelation of all parameters not related to affinity, and is equal to the dissociation constant Kd See Davies et al„ Annual Rev Biochem. 59:439-473, (1990). in some aspects, a masked cytokine described herein binds to a target protein with about the same or higher affinity upon cleavage with a protease as compared to the parental cytokine that comprises a masking oiety but does not comprise a e!eavable peptide. The target protein can be any cytokine receptor. in some embodiments, a masked cy tokine provided herein that does not comprise a cleavable peptide in the linker lias a dissociation constant (Kd) of < 1M, <150 nM, 5(100 nM, 5(50 nM, < 10 nM, <1 nM, 5(0.1 nM, 5(0.01 nM, or < 0.001 nM (e.g. 10-8 M or less, e.g. from 10-8 M to 10- 13 M, e.g., from 10-9 M to 10- 13 M) with the target protein. In some embodiments, a masked cytokine provided herein that comprises a cleavable peptide in the linker lias a dissociation constant (Kd) of <1M, 5(150 nM, < 100 nM, <50 nM, <10 nM, 5(1 nM, <0 1 nM, < 0.03 nM, or 0.001 nM (e.g. 10-8 M or less, e.g. from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M) with She target protein prior to cleavable with a protease. In some embodiments, a masked cytokine provided herein that comprises a cleavable peptide in the linker lias a dissociation constant (Kd) of<!M, <150 nM, < 100 nM, <50 nM, < 10 nM, <1 nM, <0.1 nM, <Q.01nM, or <0.001 nM (e.g. 10-8 M or less, e.g. from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M) with the target protein upon cleavage with a protease. In some embodiments, the cytokine or functional fragment thereof of amasked cytokine provided herein has a dissociation constant (Kd) of > 500M, > 250M, > 200M, > 150M, > lOOM, > SOM, > 10M, > IM, > 500 nM, > 250 iiM, > 150 rM, > 100 nM, > 50 nM, > 10 nM, > 1 iM, > 0.1 nM, > O.Ol nM, or > 0001 nM with the masking moiety of the masked c tokine in some embodiments, the cytokine or functional fragment thereof of a masked cytokine provided herein has a dissociation constant (Kd) that is between about 200M and about 50 nM, such as about or at least about 175M, about or at least about 150M, about or at least about 125M, about or at least about lOGM, about or at least about 75M, about or at least about 50M, about or at least about 25M, about or at least about 5M, about or at least about 1M, about or at least about 750 nM, about or at least about 500 nM, about or at least about 250 nM, about or at least about 150 nM, about or at least about 100 nM, about or at least about 75 nM, or about or at least about 50 nM. Assays for assessing binding affinity are well known in the art.In some aspects, masked cytokines that exhibit a desired occlusion ratio are provided. The term “occlusion ratio”as used herein refers a ratio of (a) a maximum detected level of a parameter under a first set of conditions to (b) a minimum detected valise of that parameter under a second set of conditions. In the context of a masked EL-12 polypeptide, the occlusion ratio refers to the ratio of (a) a maximum detected level of target protein (e.g., IL-12R protein) binding to the masked IL-12 polypeptide in the presence of at least one protease capable of cleaving the cieavable peptide of the masked IL-12 polypeptide to (b) a minimum detected level of target protein (e.g., 1L-12R protein) binding to the masked IL-12 polypeptide in the absence of the protease. Thus, the occlusion ratio for a masked cytokine can be calculated by dividing the EC50 of the masked cytokine pre-cleavage by the EC50 of the masked cytokine post-cleavage. The occlusion ratio of a masked cytokine can also be calculated as the ratio of the dissociation constant of the masked cytokine before cleavage with a protease to the dissociation constant of the masked cytokine after cleavage with a protease. In some embodiments, a greater occlusion ratio for the masked cytokine indicates that target protein bound by the masked cytokine occurs to a greater extent (e g., predominantly occurs) in the presence of a protease capable of cleaving the cieavable peptide of the masked cytokine than in the absence of a protease.In some embodiments, masked cytokines with an optimal occlusion ratio are provided herein. In some embodiments, an optimal occlusion ratio of a masked cytokine indicates the masked cytokine has desirable properties useful for the methods or compositions contemplated herein. In some embodiments, a masked cytokine provided herein exhibits an optimal occlusion ratio of about 2 to about 10,000, e.g., about 80 to about 100. In a further embodiment of any of the masked cytokine provided herein, the occlusion ratio is about 2 to about 7,500, about 2 to about 5,000, about 2 to about 2,500, about 2 to about 2,000, about 2 to about 1 ,000, about 2 to about 900, about 2 to about 800, about 2 to about 700, about 2 to about 600, about 2 to about 500, about 2 to about 400, about 2 to about 300, about 2 to about 200, about 2 to about 100, about 2 to about 50, about 2 to about 25, about 2 to about 15, about 2 to about 10, about 5 to about 10, about 5 to about 15, about 5 to about 20, about 10 to about 100, about 20 to about 100, about 30 io about 100, about 40 to about: 100, about 50 to about 100, about 60 to about 100, about 70 to about 100, about 80 toabout 100, or about 100 to about 1,000. In some embodiments, a masked cytokine provided herein exhibits an optimal occlusion ratio of about 2 to about 1,000. Binding of a masked IL-12 polypeptide to a target protein before cleavage and / or after cleavage with a protease can be determined using techniques well known in the art such as by ELISA.In some embodiments, a masking moiety described herein binds to a cytokine or functional fragment thereof as described herein w i th lower affinity than the affinity between the cy tokine or functional fragment thereof and a target protein (e.g., cytokine receptor). In certain embodiments, a masking moiety provided herein binds to a cytokine or functional fragment thereof as described herein with a dissociation constant (Kd) of > 500M, > 250M, > 200M, > 150M, > 100M, > 50M, > 10M, > 1M, > 500 nM, > 250 nM, > 150 nM, >300 nM, > 50 nM, > 10 nM, > 1 nM, > 0 1 nM, > 0.01 nM, or > 0.001 nM.4. MASKED IL-12 CYTOKINE PRODIJ CTION The masked cytokines described herein are prepared using techniques available in the art, exemplary methods of which are described.4.1 Antibody Production Some embodiments of the masked IL-12 cytokine comprise an antibody or fragment thereof. The following sections provide further detail on the production of antibodies and antibody fragments, variants, and derivatives thereof, that may be used in some embodiments of the masked IL-12 cytokine provided herein in some embodiments, the masked cytokine is in the form of a dimer produced by two copies of a masked II.- 12 cytokine that are associated through disulfide bonds.1. Antibody FragmentsThe present invention encompasses, in some embodiments, antibody fragments. The antibody fragments can be any antibody fragments, such as an Fc domain, a portion of the heavy chain, a portion of the light chain, an Fab, an Fv, or an scFv, among other fragments. Antibody fragments may be generated by traditional means, such as enzymatic digestion, or by recombinant techniques, in certain circumstances, there are advantages of linking antibody fragments, rather than whole antibodies, to the masked cytokines described herein. For a revie of certain antibody fragments, see Hudson et al. (2003) Nat Med. 9:129- 134.Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al.. Journal ofBiochemical arid Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli and other cell types, such as HEK293 and CHQ cells, thus allowing the facile production of large amounts of these fragments. Alternatively, Fab-SH fragments can be directly recovered from culture media and chemically coupled to form F(ab)2 fragments (Carter et al., Bio / Technology 10: 163-167 (1992)). According to another approach, F(ab)2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab)2 fragments with increased in vivo half-life comprising FcRN / salvage receptor binding epitope residues are described in U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments for use in the masked cytokines will be apparent to the skilled practitioner. In certain embodiments, a masked cytokine comprises a single drain Fv fragment (scFv). See WO 93 / 16185; U.S. Pat. Nos. 5,571,894; and 5,587,458. scFv fusion proteins may be constructed to yield fusion of an effector rotein at either the amino or the carboxy terminus of an scFv. See Antibod Engineering, ed. Borrebaeck, supra. Also, in some embodiments, bi- scFv comprising two scFvs linked via a polypeptide linker can be used with the masked cytokines.The present invention includes, in some embodiments, a linear antibody (e.g., as described in U.S. Pat. No. 5,641,870) or a single chain immunoglobulin comprising heavy and light chain sequences of the antibody linked via an appropriate linker Such linear antibodies or immunoglobulins may be monospecific or bispecific. Such a single drain immunoglobulin can be dimerized to thereby maintain a structure and activities similar to those of the antibody, which is originally atetramer. Also, in some embodiments, the antibody or fragment thereof may be an antibody that has a single heavy chain variable region and has no light drain sequence. Such an antibody is called a single domain antibody (sdAb) or a nanobody. These antibodies are also encompa ssed in the meaning of the functional fragment of the antibody according to the present invention. Antibody fragments can be linked to the masked cytokines described herein according to the guidance provided herein.2. Humanized AntibodiesThe invention encompasses, in some embodiments, humanized antibodies or antibody fragments thereof in some embodiments, the humanized antibodies can be any antibodies, including any antibody fragment. Various methods for humanizing non-human antibodies are known in the art. For example, a humanized antibody can have one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import”variable domain Humanization can be essentially performed following the method of Winter (Jones et al. (1986) Nature 321:522-525; Riechmann et al. (1988) Nature 332:323-327; Verhoeyen et al. (1988) Science 239: 1534- 1536), by substituting hypervariable region sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567) wherein substantially less than an intact human variable domain has been substitutedby the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypeivariab!e region residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. Humanized antibodies can be linked to the masked cy tokines described herein according to the guidance provided herein.3. Human AntibodiesHuman antibodies of some embodiments of the invention can be constructed by combining Fv clone variable domain sequence(s) selected from human-derived phage display libraries with known human constant domain sequences(s). Alternatively, human monoclonal antibodies of some embodiments of the invention can be made by the hybridoma method, e.g., by using mouse, rat, bovine (e.g., cow), or rabbit cells, for example, to produce the human monoclonal antibodies. In some embodiments, the human antibodies and human monoclonal antibodies can be antibodies that bind to any antigen. In some embodiments, human monoclonal antibodies of the invention cart be made by immunizing a non-human animal that comprises human immunoglobulin loci with the target antigen, and isolating the antibody from the immunized animal or from cells derived from the immunized animal. Examples of suitable non-human animals include a transgenic or tianschromosomic animal, such as HuMAb Mouse© (Medarex, Inc.), KM Mouse®, “TC mice,” and Xenoniouse™ See, e.g., Lonberg, et al (1994) Nature 368: 856-859; Fishwild, D. et al. (1996) Nature Biotechnology 14: 845-851: WO2002 / 43478; U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584; 6,162,963; and Tomizuka et al. (2000) Proc. Natl. Acad. Sci. USA 97:722-727.

[0420] Human myeloma and murine-buman heteromyeloma cell lines for the production of human monoclonal antibodies have been described, for example, by Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al, Monoclonal Antibody Production Techniques and Applications, pp 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerneret al, J. Immunol , 147: 86 (1991). Human antibodies can be linked to the masked cy tokines described herein according to the guidance provided herein.4. Bispecific AntibodiesBispecific antibodies are monoclonal antibodies that have binding specificities for at least two different antigens. In certain embodiments, bispecific antibodies are human or humanized antibodies. In some embodiments, one of the binding specificities is for a first antigen and the other binding specificity is for a second antigen, which may be either two different epitopes on the same target protein, or two different epitopes on two different target proteins. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express the first antigen and / or the second antigen. Bispecific antibodies may also be used to recruit cells, such as T cells or natural killer cells, to kill certain cells, e.g , cancer cells. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g. F(ab')2 bispecificantibodies). Bispecific antibodies can be linked to the masked cytokines described herein according to the guidance provided herein.Methods for making bispecific antibodies are known in the art. See Milstein and Cueilo, Nature, 305: 537 (1983). WO 93 / 08829 published May 13, 1993, Traunecker et al, EMBO J., 10: 3655 (1991): Kontennann and Brinkmann, Drag Discovers' Today, 20(7):838-847. For further details of generating bispecific antibodies see, for example, Sureshet al.. Methods in Enzymology, 121:210 (1986). Bispecific antibodies include cross-linked or “heteroconjugate” antibodies. For example, one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Heteroconjugate antibodies may be made using any convenient cross-linking method. Suitable cross-linking agents are well known in the art, and are disclosed in U S. Pat. No. 4,676,980, along with a number of cross-linking techniques.5, Single-Domain AntibodiesIn some embodiments, a single-domain antibody is linked to the masked cytokine in accordance with the guidance provided herein. The single-domain antibody can be any antibody. A single-domain antibody is a single polypeptide chain comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody In certain embodiments, a single -domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.: see, e.g., U.S. Pat. No. 6,248,516 Bl). in some embodiments, a single-domain antibody consists of all or a portion of the heavy chain variable domain of an antibody. In some embodiment, the single domain antibody is a camelid-derived antibody obtained by immunization of a came!id with the target antigen. In some embodiments, the single domain antibody is a shark-derived antibody obtained by immunization of a shark with the target antigen. In some embodiments, the single domain antibody is a Nanobody (see, e.g , WO 2004041865 A2 and US20070269422A1).6. Antibody VariantsIn some embodiments, amino acid sequence niodification(s) of the antibodies or fragments thereof described herein are contemplated. For example, it may be desirable to improve the FcRn- binding affinity and / or pH-dependent FcRn-binding affinity of the antibody it may also be desirable to promote heterodimerizalion of antibody heavy chains by introducing certain amino acid modifications. Methods for promoting heterodimerizalion of antibody chains, including certain modifications that can be made to facilitate heterodimerization, is described by Klein et al. (2012), MAbs, 4(6): 653-663Amino acid sequence variants of the antibody may be prepared by introducing appropriate changes into tire nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of, residues within the amino acidsequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses tire desired characteristics. The amino acid alterations may he introduced in the subject antibody amino acid sequence at the time that sequence is made.A useful method for identifica tion of certain residues or regions of the antibody that are preferred locations for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081-1085. Here, a residue or group of target residues are identified (e.g., charged residues such as arg, asp, his, lys, and glu) and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to affect the interaction of the amino acids with antigen. Those amino acid locations demonstrating functional sensitivity to the substitutions then are refined by introducing further or other variants at, or for, the sites of substitution. Thus, while the site for introducing an a ino acid sequence variation is predetermined, the nature of the mutation per se need not be predetermined. For example, to anal ze the performance of a mutation at a given site, ala scanning or random mutagenesis is conducted at tire target codon or region and the expressed immunoglobulins are screened for the desired activity.Amino acid sequence insertions inelude amino- and / or carboxyl-terminal fusions ranging til length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N- terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the Ivor C-terminus of the antibody to an enzyme or a polypeptide which increases the serum half-life of the antibody. in some embodiments, the masked cytokine is modified to eliminate, reduce, or otherwise hinder protease cleavage near the hinge region. The “hinge region” of an IgG is generally defined as includi ng E216 and terminating at P230 of human IgGl according to the EU index as in Kabat, but, functionally, the flexible portion of the chain may be considered to include additional residues termed the upper and lower hinge regions, such as from E216 to G237 (Roux etal., 1998 J Immunol 161:4083) mid the lower hinge has been referred to as residues 233 to 239 of die Fc region where FeyK binding was generally attributed. Modifications to any of the masked cy tokines described herein, can be performed, for example, according to the methods described in US 20150139984A1, which is incorporated herein by reference, as well as by incorporating any of the modifications described therein.In some embodiments, FcRn mutations that improve pharmacokinetics include, but are not limited to, M428L, T250Q / M428L, M252Y / S254T / T256E, P257I / N434H, D376V / N434H, P257I / Q3111, N434A, N434W, M428L / N434S, V259I / V308F, M252Y / S254T / T256E, V259I / V308F / M428L, T307Q / N434A, T307Q / N434S, T307Q / E380A / N434A, V308P N434A, N434H, V308P. In some embodiments, suchmutations enhance antibody binding to FcRn at low pH but do not change die antibody affinity at neutral pH.In certain embodiments, an antibody or fragment thereof is altered to increase or decrease the extent to which the antibody is glycosylated. Glycosyiation of polypeptides is typically either N-linked or Odinked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side drain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosyiation site. O-linked glycosyiation refers to the attachment of one of the sugars N- aceytlgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxyf sine may also be used.Addition or deletion of glycosyiation sites to the masked cytokine is conveniently accomplished by altering tire amino acid sequence such that one or more of the above-described tripeptide sequences (for N-linked glycosyiation sites) is created or removed. The alteration may also be made by the addition, deletion, or substitution of one or more serine or threonine residues to the sequence of the original antibody (for O- linked glycosyiation sites).Where the antibody or fragment thereof comprises an Fe region, the carbohydrate attached thereto may be altered. For example, antibodies with a mature carbohydrate structure that lacks fucose atached to an Fc region of the antibody are described in US Pat Appl No US 2003 / 0157108 (Presta, I..). See also US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Antibodies with a bisecting N- acetylglucosamine (GlcNAc) in the carbohydrate attached to an Fc region of the antibody are referenced in WO 2003 / 011878, Jean-Mairet et al. and U.S. Pat. No 6,602,684, Umana et al. Antibodies with at least one galactose residue in the oligosaccharide attached to an Fc region of the antibody are reported in WO 1997 / 30087, Patel et al. See, also, WO 1998 / 58964 (Raju, S.) and WO 1999 / 22764 (Raju, S.) concerning antibodies with altered carbohydrate attached to the Fc region thereof. See also US 2005 / 0123546 (Umana et al.) on antigenbinding molecules with modified glycosyiation.In certain embodiments, a glycosyiation variant comprises an Fc region, wherein a carbohydrate structure attached to the Fc region lacks fucose or has reduced fucose. Such variants have improved ADCC function. Optionally, the Fc region further comprises one or more amino acid substitutions therein which further improve ADCC, for example, substitutions at positions 298, 333, and or 334 of the Fc region (Eu numbering of residues). Examples of publications related to “defucosylated” or “fucose-deficient” antibodies include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; Okazaki et al. J.Mol. Biol. 336:1239-1249 (2004); Yamane-Ohiuiki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines producing defucosylated antibodies include Lee 13 CHQ cells deficient m protein fucosylation (Ripka el al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 / 0157108 AL Presta, L; and WO 2004 / 056312 Al, Adams et al, especially at Example 11), and knockout cell lines, such as alpha-3,6- fucosy {transferase gene, FUT8, knockout CHO cells (Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004)), and cells overexpressing (31,4-N-acetylglycosminyltransferase Ill (GriT-lIl) and Golgi p- mannosidase P (Manli) in any of the embodiments herein, the masked cytokine can be engineered to improve antibody -dependent cell-mediated cytotoxicity (ADCC) activity. In some embodiments, the masked cytokine may be produced in a cell line having a alphal,6-fucosyltransferase (Fut8) knockout. In some embodiments, the host cells have been modified to have reduced intrinsic alpha! ,6-fucosylation activity Examples of methods for modifying the fucosylation pathways in mammalian host cells can be found in, e.g., Yamane-Ohnuki and Satoh, MAbs, 1(3): 230-236 (2009), the contents of which are incorporated herein by reference. Examples of methods and compositions for partially or completely inactivating the expression of the FUT8 gene can be found in, e.g., US Pub. No. 20160194665A 1; WO2006133148A2, the contents of which are incorporated herein by reference. In some embodiments, the masked cytokine is produced in the Lecl3 variant of CHO cells (see, e g , Shields et al., I Biol Ghent, 277(30):26733-40 (2002)) or the YB2 / 0 cell line having reduced FUT8 activity (see, e.g., Shinkawa et al, J. Biol. Ghent, 278(5): 3466-73 (2003)). in some embodiments, small interfering RNA (siRN A) against genes relevant to alpbal,6-fucosylation can be introduced (see, e.g, Mori et al, Biotechnol. Bioeng. 88(7): 901-908 (2004); Imai-Nishiya et al, BMC Biotechnoi 7: 84 (2007); Omasa et al, J. Biosci. Bioeng, 106(2): 168-Ί73 (2008)). In some further embodiments, the masked cytokine may be produced in a cell line overexpressing |31,4-N- acetylglycosminyltransferase IP (GnT-III). In further embodiments, the cell line additionally ove rexpresses Golgi p-mannosidase IT (Manli). In some of the embodiments herein, the masked cytokine may comprise at least one amino acid substitution in the Fc region that improves ADCC activity.In some embodiments, the masked cytokine is altered to improve its serum half-life. To increase the serum half-life of the cytokine, one may incorporate a FcRN / salvage receptor binding epitope into a linked antibody (especially an antibody fragment) as described in U.S. Pat. No. 5,739,277, for example. As used herein, the term “salvage receptor binding epitope” refers to an epitope of the Fc region of an IgG molecule (e.g, IgGl, IgG2, IgG3, or lgG4) that is responsible for increasing the in vivo serum half-life of the IgG rno3ecjde (US 2003 / 0190311, U.S. Pat. No. 6,821,505; U.S. Pat. No. 6,165,745; U.S. Pat. No. 5,624,821; U.S. Pat No 5,648,260; U.S. Pat No. 6,165,745; U.S Pat. No. 5,834,597).Another type of variant is an amino acid substitution variant. These variants have at least one amino acid residue in the antibody molecule replaced by a different residue. Sites of interest for substitutional mutagenesis include the hypervariable regions, but FR alterations are also contemplated. Conservativesubstitutions are shown in Table 3 under die heading of “preferred substitutions.” if such substitutions result in a desirable change in biological activity, then more substantial changes, denominated “exemplary substitutions” in Table 3, or as further described below in reference to amino acid classes, may be introduced and the products screened.Substantial modifications in the biological properties of Hie antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the cltarge or hydrophobicity of the molecule at the target site, or c) the bulk of the side chain. Amino acids may be grouped according to similarities in the properties of their side chains (in A. L. Lelminger, in Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975)):(1) non-polar: Ala (A), Vai (V), Leu (L), lie (Ϊ), Pro (P), Phe (F), Trp (W), Met (M) (2) uncharged polar: Giy (G), Ser (S), Thr (T), Cys (C) Tyr (Y), Asn (N), Gin (Q)(3) acidic: Asp (D), Glu (E)(4) basic: Lys (K), Arg (R), His (H)Alternatively, naturally occurring residues may be divided into groups based on common side-chain properties:(1) hydrophobic: Norleucine, Mel, Ala, Val, Leu, he;(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;(3) acidic: Asp, Glu;(4) basic: His, Lys, Arg;(5) residues that influence drain orientation: Gly, Pro;(6) aromatic: Trp, Tyr, Phe.Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, into the remaining (non-conserved) sites.Another type of substitutional variant involves the substitution of a naturally occurring amino acid residue for a non-naturally occurring amino acid residue Non-naturai!y occurring amino acid residues can be incorporated, e.g., through tRNA recoding, or through any of the methods as described, e.g., in WO 2016154675A1, which is incorporated herein by reference.One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variants) selected for further development will have modified (e.g., improved) biological properties relative to the parent antibody from which they are generated. A convenient way for generating such substitutional variants involves affinity maturation using phage display, yeast display, or mammalian display. Briefly, several hypervariabie region sites (e.g., 6-7 sites) are mutated to generate all possible amino acid substitutions at each site. The antibodies thus generated are displayed from filamentous phage particles as fusions to at least part of a phage coat protein (e.g., the gene III product of Ml 3) packaged within each particle. The phage-displayed variants are then screened for their biological activity (e.g., bi nding affinity). In order to identify candidate hypervariabie region sites for modification, scanning mutagenesis (e.g., alanine scanning) can be performed to identify hypervariabie region residues contributing significantly to antigen binding. Alternatively, or additionally, it may be beneficial to analyze a crystal structure of the antigen- antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighbouring residues are candidates for substitution according to techniques known in the art, including those elaborated herein. Once such valiants are generated, the panel of variants is subjected to screening using techniques known in the art, including those described herein, and antibodies with superior properties in one or more relevant assays may be selected for further development.Nucleic acid molecules encoding amino acid sequence variants of the masked cytokines are prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the antibody, for example.It may be desirable to introduce one or more ainino acid modifications in an Fc region of antibodies of the invention, thereby generating anFc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions including that of a hinge cysteineIn some embodiments, a masked cytokine provided herein includes an antibody or fragment thereof having an IgGl, lgG2, IgG3, or IgG4 isotype with enhanced effector function. In some embodiments, a masked cytokine provided herein includes an antibody or fragment thereof having an IgGl isotype with enhanced effector function. In some embodiments, a masked cytokine provided herein has an IgGl isotype with enhanced effector function. In some embodiments, the masked cytokine is afucosylated. In some embodiments, the masked cytokine lias increased levels of mannose moieties. In some embodiments, the masked cytokine lias increased levels of bisecting glycan moieties. In some embodiments, the IgGl comprises amino add mutations.In some embodiments, a masked cytokine provided herein includes an antibody having an IgGl iso type (e.g., a human IgGl isotype). In some embodiments, the IgGl comprises one or more amino acid substitutions that enhance effector function. In one embodiment, the IgGl comprises the amino acid substitutions S298A, E333 A, and K334A wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment, the IgGl comprises the amino acid substitutions S239D and I332E wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment, the IgGl comprises the amino add substitutions S239D, A330L, and I332E wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment, tire IgGl comprises the amino acid substitutions P247I and A339D or A339Q wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment, the IgGl comprises the amino acid substitutions D280H, K290S with or without S298D or S298V wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment, the IgGl comprises the amino acid substitutions F243L, R292P, and Y300L wherein die a ino acid residues are numbered according to die EU index as in Kabat. In one embodiment, die IgGl comprises tire amino acid substitutions F243L, R292P, Y300L, and P396L wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment the IgGl comprises the ainino acid substitutions F243L, R292P, Y300L, V305I, and P396L wherein the amino acid residues are numbered according to the EU index as in Kabat In one embodiment, the IgGl comprises the amino acid substitutions G236A, S239D, and I332E wherein the amino acid residues are numbered according to the EU index as in Kabat. In one embodiment, the IgGl comprises the amino acid substitutions K326A and F.333A wherein the amino acid residues are numbered accordi ng to the EU index as in Kabat. In one embodiment, the IgGl comprises the amino acid substitutionsK326W and E333S wherein the amino acid residues are numbered according to the EU index as in Rabat, in one embodiment, the IgGl comprises the amino acid substitutions K290E, S298G, T299A, with or without K326E wherein the amino acid residues are numbered according to the EU index as in Rabat in one embodiment, the IgGl comprises the amino acid substitutions K290N, S298G, T299A, with or without K326E wherein the amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitution K334V wherein the amino acid residues are numbered according to the EU index as in Rabat In one embodiment, die IgGl comprises the ainino acid substitutions L235S, S239D, and K334V wherein the amino acid residues are numbered according to tine EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitutions K334V and Q331M, S239D, F243V, E294L, or S298T wherein the amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl compri ses the amino acid substitutions E23.31,, Q311M, and K334V wherein the amino acid residues are numbered according to tire EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitutions L234I, Q311M, and K334V wherein tire amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitutions K334V and S298T, A330M, or A33 OF wherein the amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl comprises the ainino acid substitutions K334V, Q311M, and either A330M or A330F wherein the amino acid residues are numbered according to the EU index as in Rabat In one embodiment, the IgGl comprises the amino acid substitutions K334V, S298T, and either A330M or A330F wherein the amino acid residues are numbered according to the EU index as in Rabat in one embodiment, the IgGl comprises the amino acid substitutions K334V, S239D, and either A330M or S298T wherein the amino acid residues are numbered according to the EU index as in Rabat in one embodiment, the IgGl comprises the amino acid substitutions L234Y, Y296W, and K290Y, F243 V, or E294L wherein the amino acid residues are numbered according to the EU index as in Rabat In one embodiment, tire IgGl comprises the amino acid substitutions Y296W and either L234Y or K290Y wherein the amino acid residues are numbered according to the EU index as in Rabat In one embodiment, the IgGl comprises the ainino acid substitutions S239D, A330S, and I332E wherein the amino acid residues me numbered according to the EU index as in Rabat. in some embodiments, the IgGl comprises one or more amino acid substitutions that decrease or inhibit effector function. In one embodiment, the IgGl comprises the amino acid substitution N297A, N297G, or N297Q wherein the amino acid residues are numbered according to the EU index as in Rabat in one embodiment, the IgGl comprises the amino acid substitution L234A or L235A wherein the amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitutions C220S, C226S, G229S, and P238S wherein the amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitutions C226S, C22.9S, E233P, L234V, and L235A wherein the amino acid residues are numbered according to the EU index as in Rabat. In one embodiment, the IgGl comprises the amino acid substitutions L234F, L2.35E, and P331 S wherein the a ino acid residues are numbered according to the EU index as in Rabatin one embodiment, the IgGl comprises the amino acid substitutions S267E and L328F wherein the amino acid residues are numbered according to the EU index as in Rabat.In accordance with this description and the teachings of the art, it is contemplated that in some embodiments, an antibody or fragment thereof of the masked cytokine may comprise one or more alterations as compared to the wild type counterpart antibody, e.g. in the Fc region. For example, it is thought that certain alterations can be made in the Fc region that would result in altered (i.e., either improved or diminished) Clq binding and / or Complement Dependent Cytotoxicity' (CDC), e.g., as described in W099 / 51642. See also Duncan & Winter Nature 322:738-40 (1988); U.S. Pat. No. 5,648,260; U.S. Pat No. 5,624,821; and W094 / 29351 concerning other examples ofFc region variants. WO00 / 42072 (Presta) and WO 2004 / 056332 (Lowman) describe antibody variants with improved or diminished binding to FcRs The content of these patent publications are specifically incorporated herei n by reference. See also Shields et al. J. Biol. Chem. 9(2): 6591-6604 (2001). Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al, I. Immunol. 117:587 (1976) and Kim et al., j. Immunol. 24:249 (1994)), are described in US2005 / 0014934A1 (Hinton et al. ). These antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Polypeptide valiants with altered Fc region amino acid sequences and increased or decreased Clq binding capability' are described in U S. Pat No. 6, 194,55 IB 1, W099 / 51642. The contents of those patent publications are specifically incorporated herein by reference. See, also, Tdusogie et al. J. Immunol. 164: 4178-4184 (2000)4.2 Masked iL-12 Cytokine-Drag ConjugatesThe invention also provides masked IL-12 cytokine -drug conjugates (MCDCs) comprising a masked IL- 12 cytokine provided herein, winch can be any IL-12 masked cytokine disclosed herein, conjugated to one or more agents. In some embodiments, the one or more agents is a cytotoxic agent, such as a chemotherapeutic agent or drag, growth inhibitory agent, toxin (e.g., protein toxin, enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes. In some embodiments, the one or snore agents is an immune stimulant in some embodiments, tire one or more drugs conjugated to the masked IL-12 cytokine includes, but is not limited to, a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 Bl); an auristatin such as monometliyiauristatm drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et ak, Cancer Res. 53:3336-3342 (1993); and Lode et ak, Cancer Res. 58:2925-2928 (1998)); an anthracy cline such as daunomycin or doxorubicin (see Kratz et ak, Current Med. Chem. 13 :477- 523 (2006); Jeffrey et ak, Bioorgairic & Med. Chem. Letters 16:358-362 (2006); Torgov et ak, Bioconj.Chem. 16:717-721 (2005); Nagy et ak, Proc. Natl Acad. Sci. USA 97:829-834 (2000); DubowcMk et ak, Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King el ak, J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paditaxel, iarotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065. in another embodiment, the one or more drags conjugated to the masked IL-12 cytokine includes, but is not limited to, an inhibitor of tubulin polymerization (e g , maytansinoids and auristatins), DNA damaging agents (e.g., pyrrolobenzodiazepine (PBD) dimers, caliclieamicins, duocarmycins and indo- iinobenzodiazepine dimers), and DNA synthesis inhibitors (e.g., exatecan derivative Dxd).In another embodiment, a masked IL-12 cytokine-drug conjugate comprises a masked II, -12 cytokine as described herein conjugated to an enzymatically active toxi n or fragment thereof, including, but not limited to, diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A cliain (from Pseudomonas aeruginosa), riein A chain, abrin A cliain, modeccin A chain, alptia-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, cretin, sapaonaria officimlis inhibitor, gelonin, rmtogellin, restrictocin, plienomycin, enomycin, and the tricothecenes.In another embodiment, a masked IL-12 cytokine-drug conjugate comprises a masked IL-12 cytokine as described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At211,1131 ,1125 , Y90, Kel86, Rel88, Sml53, B1212, P32, Pb212 and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15 ox gen-17, gadolinium, manganese or iron. in some embodiments, a masked IL-12 cytokine-drug conjugate comprises a masked IL-12 cytokine as described herein conjugated to one or more immune stimulants. In some embodiments, the immune stimulant is a stimulator of interferon genes (STING) agonist or a toll-like receptor (TER) agonist.The S TING agonist can be any agonist of STING. In some embodiments, the STING agonist is a cyclic dinucleotide (CDN). The CDN can be any CDN or derivative or variant thereof. In some embodiments, the STING agonist is a CDN selected from the group consisting of cGAMP, c-di- AMP, c-di-GMP, cAIMP, and c-di-IMP. In some embodiments, the STING agonist is a derivative or variant of a CDN selected from the group consisting of cGAMP, c-di-AMP, c-di-GMP, cAIMP, and c-di- IMP. In some embodiments, tire STING agonist is 4-(2-chloro-6-f]uorobenzyl)-N-(furan-2-ylniethyl)-3- oxo-3,4-dihydro-2H- benzo[b][l,4]thiazine-6-cafboxamide, or a derivative or variant thereof. See, e.g., Salt et ai. (2015) PloSPaihog, 11(12): e!005324.The TLR agonist can be an agonist of any TLR, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, or TLR10. In some embodiments, the TLR agonist is an agonist of a TLR expressed on the cell surface, such as TLR1, TLR2, TLR4, or TLR5. in some embodiments, the TLR agonist is an agonist of a TLR expressed intracellularly, such as TLR 3, TLR7, TLR8, TLR9, or TLR 10.Conjugates of a masked TL-12 cytokine and a cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinitmdyl-4- (N-maleimidomethyl) cyclohexane- 1-carboxy late (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HC1), active esters (such as disuccinimidyl suberate), aldehydes (such as gluiaraldehyde), bis-azido compounds (such as bis (p- azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediaxnme), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Viteta et ah. Science 238:1098 (1987). Carbon- 14-labeled l-isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to an antibody. See W094 / 11026. The linker may be a “cleavahle linker” facilitating release of a cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et ah, Cancer Res. 52: 127-131 ( 1992); U.S. Patent No. 5,208,020) may be used.The MCDCs herein expressly contemplate, but are not limited to such conjugates prepared with cross- linker reagents including, but not limited to, BMPS, EMCS, GMBS, HB VS, LC-SMCC,MBS, MPBH, SBAP, SIA, SLAB, SMCC, SMPB, SMPH, sulfo-EMCS, suifo-GMBS, sulfo-KMUS, sulfo- MBS, sulfo-SIAB, su!fo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsuifonejbenzoate) which are commercially available (e.g., from Pierce Biotechnology, rite., Rockford, IL., U.S. A).4.3 Vectors, Host Cells, an Recombinant MethodsFor recombinant production of a IL-32 masked cytokine of the invention, the one or snore nucleic acids encoding it is isolated and inserted into a replicable vector for further cloning (amplification of theDNA) or for expression. DNA encoding the masked 1L.-12 cytokine, including components thereof, is readily isolated and sequenced using conventional procedures. Many vectors are available. The choice of vector depends in part on the host cell to be used. Generally, host cells are of either prokary otic or eukaryotic (generally mammalian) origin. It will be appreciated that constant regions of any isotype of antibody or fragment thereof, when applicable, can be used for this purpose, including IgG, lgM, IgA, IgD, and IgE constant regions, and that such constant regions can be obtained from any human or animal species in some embodiments, one vector is used to encode the IL-12 masked cytokine in some embodiments, morethan one vector is used to encode the masked IL-12 cytokine.1. Generating Masked IL-12 Cytokines Using Prokaryotic Host Ceils a. Vector ConstructionPolynucleotide sequences encoding polypeptide components of the masked cytokines of the invention can be obtained using standard recombinant techniques. Desired pol nucleotide sequences of an antibody or antibody fragment thereof may be isolated and sequenced from antibody producing cells such as hybridonia cells. Alternatively, pol nucleotides can be synthesized using nucleotide synthesizer or PGR techniques, or obtained from other sources. Once obtained, sequences encoding the components of the masked cytokine are inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in prokaryotic hosts. Many vectors that are available and known in the art can be used for the purpose of the present invention. Selection of an appropriate vector will depend mainly on the size of the nucleic acids to be inserted into the vector and the particular host cell to be transformed with the vector. Each vector contains various components, depending on its function (amplification or expression of heterologous polynucleotide, or both) and its compatibility with the particular host cell in which it resides. The vector components generally include, but are not limited to: an origin of replication, a selection marker gene, a promoter, a ribosome binding site (RBS), a signal sequence, the heterologous nucleic acid insert and a transcription terminator sequence. in general, plasmid vectors containing replicon and control sequences which are derived from species compatible with the host cell are used in connection with these hosts. The vector ordinarily carries a replication site, as well as marking sequences which are capable of providing phenotypic selection in transformed cells. For example, E. coli is typically transformed using pBR322, a plasmid derived from an E. coli species. pBR322 contains genes-encoding ampieillin (Amp) and tetracycline (Tet) resistance and thus provides easy means for identifying transformed cells. pBR322, its derivatives, or other microbial plasmids or bacteriophage may also contain, or be modified to contain, promoters which can be used by the microbial organism for expression of endogenous proteins Examples of pBR322 derivatives used for expression of particular antibodies are described in detail in Carter et ah, U S. Pat. No. 5,648,237In addition, phage vectors containing replicon and control sequences that are compatible with the host microorganism can be used as transforming vectors in connection with these hosts. For example, bacteriophage such as 7GEM.TM.-11 may be utilized in making a recombinant vector which can be used to transform susceptible host cells such as E. coli LE392.The expression vector of the invention may comprise tw o or more promoter-cistron pairs, encoding each of the polypeptide components. A promoter is an untranslated regulatory' sequence located upstream (51) to a cistronthat modulates its expression. Prokaryotic promoters typically fall into two classes, inducible andconstitutive. Inducible promoter is a promoter that initiates increased levels of transcription of the cistron under its control in response to changes in the culture condition, e.g. the presence or absence of a nutrient or a change in temperature.A large number of promoters recognized by a variety of potential host cells are well known. The selected promoter can be operably linked to cistron DNA encoding either drain of the masked cy tokine by removing the promoter from the source DNA via restriction enzyme digestion and inserting the isolated promoter sequence into the vector of the invention Both the native promoter sequence and many lieterologous promoters may be used to direct amplification and / or expression of the target genes.In some embodiments, heterologous promoters are utilized, as they generally permit greater transcription and higher y ields of expressed target ge ne as compared to the native target polypeptide promoter.Promoters suitable for use with prokaryotic hosts include the PhoA promoter, the [3- galactamase and lactose promoter systems, a tryptophan (tip) promoter system and hybrid promoters such as the tac or the tec promoter. However, other promoters that are functional in bacteria (such as other kno n bacterial or phage promoters) are suitable as well. Their nucleotide sequences have been published, thereby enabling a skilled worker operably to ligate them to cistrons encoding, for example, the target light and heavy chains for masked cytokines comprising a light and heavy chain (Siebeniist et al. (1980) Cell 20: 269) using linkers or adaptors to supply any required restriction sites.In one aspect of the invention, each cistron within the recombinant vector comprises a secretion signal sequence component that directs translocation of the expressed polypeptides across a membrane. In general, the signal sequence may be a component of the vector, or it may be a part of the target polypeptide DN A that is inserted into the vector. The signal sequence selected for the purpose of this invention should be one that is recognized and processed (i.e. cleaved by a signal peptidase) by the host cell For prokaryotic host cells that do not recognize and process the signal sequences native to the heterologous polypeptides, the signal sequence is substituted by a prokaryotic signal sequence selected, for example, from the group consisting of the alkaline phosphatase, penicillinase, Ipp, or heat-stable enterotoxin ΪI ( STI1) leaders, LamB, PhoE, PelB, QmpA and MBP. In one embodiment of the invention, the signal sequences used in both cistrons of the expression system are STII signed sequences or variants thereof.In another aspect, the production of the polypeptide components according to the invention can occur in the cytoplasm of the host cell, and therefore does not require the presence of secretion signal sequences within each cistron. In that regard, for embodiments comprising immunoglobulin light and heavy chains, for example, the light and heavy drains are expressed with or without the sequences for the masking moiety, linker sequence, etc., folded and assembled to form functional immunoglobulins within the cytoplasm. Certain host strains (e.g., the E. coli trxB -strains) provide cytoplasm conditions that are favorable for disulfide bond formation, thereby permitting proper folding and assembly of expressed protein subunits.Prctba and Plucklhun Gene, 159:203 ( 1995).Masked cytokines of the invention can also be produced by using an expression system in which the quantitative ratio of expressed polypeptide components can be modulated in order to maximize the yield of secreted and properly assembled antibodies of the invention. Such modulation is accomplished at least in part by simultaneously modulating translational strengths for the polypeptide components.Prokaryotic host cells suitable for expressing masked cytokines of the invention include Archaebacteria and Eubacteria, such as Gram-negative or Gram-positive organisms. Examples of useful bacteria include Escherichia (e.g, E. coli), Bacilli (e.g., B. subtilis), Enterobacteria, Pseudomonas species (e.g., P. aeruginosa). Salmonella typhimurium, Serratia marcescans, Klebsiella, Proteus, Shigella, Rhizobia, Vitreoscilla, or Paracoccus. In one embodiment, gra -negative cells are used. In one embodiment, E coli cells are used as hosts for the invention. Examples of E. coli strains include strain W311Q (Bachmann, Cellular and Molecular Biolog , vo!. 2 (Washington, D. C. : American Society for Microbiology, 1987), pp. 1190-1219; ATCC Deposit No. 27,325) and derivatives thereof, including strain 33D3 having genotypeW3110 AfhuA (AtoiiA) ptr3 lac Iq lacLS AompTA(mnpc-fepE) degP41 kanR (U.S. Pat. No. 5,639,635). Other strains and derivatives thereof, such as E. coli 294 (ATCC 31,446), E. coli B, E. colik 1776 (ATCC 31,537) and E. coli RV308(ATCC 31,608) are also suitable These examples are illustrative rather than limiting. Methods for constructing derivatives of any of the above-mentioned bacteria having defined genotypes are known in the art and described in, for example, Bass et ah, Proteins, 8:309-314 (1990) It is generally necessary to select the appropriate bacteria taking into consideration replicability of the rep] icon in the cells of a bacterium. For example, E. coli, Serratia, or Salmonella species can be suitably used as the host when well-known plasmids such as pBR322, pBR325, pACYC177, orpKN410 are used to supply the replicoa Typically, the host cell should secrete minimal amounts of proteolytic enzymes, and additional protease inhibitors may desirably be incorporated in the cell culture. b. Masked Cytokine ProductionHost cells are transformed with the above-described expression vectors and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.Transformation means introducing DNA into the prokaryotic host so that the DNA is replicable, either as an extrachromosomal element or by chromosomal integrant. Depending on the host cell used, transformation is done using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride is generally used for bacterial cells that contain substantial cell- wall barriers. Another method for transformation employs polyethylene glycol / DMSO. Yet another technique used is electroporation.Prokaryotic cells used to produce the masked cytokines of the invention Eire grown in media known in the art and suitable for culture of the selected host cells. Examples of suitable media include luna broth (LB) plus necessary nutrient supplements. In some embodiments, the media also contains a selection agent, chosen based on the construction of the expression vector, to selectively permit growth of prokaryotic cells containing tire expression vector. For example, ainpicillin is added to media for growth of ceils expressing ampicillin resistant geneAny necessaiy supplements besides carbon, nitrogen, and inorganic phosphate sources may also be included at appropriate concentrations introduced alone or as a mixture with another supplement or medium such as a complex nitrogen source. Optionally, the culture medium may contain one or more reducing agents selected from the group consisting of glutathione, cysteine, cystamine, ihiogiy collate, dithioerythritol and ditbiothreitol. The prokaryotic host cells are cultured at suitable temperatures. In certain embodiments, for E. coii growth, growth temperatures range from about 20° C. to about 39° C; from about 25° C. to about 37° C.; or about 30° C. The pH of the medium may be arty pH ranging from about 5 to about 9, depending mainly on the host organism. In certain embodiments, for E coii, the pH is from about 6.8 to about 7.4, or about 7.0. if an inducible promoter is used in the expression vector of the invention, protein expression is induced under conditions suitable for the activation of the promoter. In one aspect of the invention, Pho A promoters are used for controlling transcription of the polypeptides. Accordingly, the transformed host cells are cultured in a phosphate-limiting medium for induction In certain embodiments, the phosphate-limiting medium is the C.R.A.P. medium (see, e.g., Simmons et ah, J Immunol Methods (2002), 263:133-147). A variety of other inducers may be used, according to tire vector construct employed, as is know n in the art. in one embodiment, the expressed masked cytokines of the present invention are secreted into and recovered from the periplasm of the host cells. Protein recoveiy typically involves disrupting the microorganism, generally by such means as osmotic shock, sonication or lysis. Once cells are disrupted, cell debris or whole ceils may be removed by centrifugation or filtration. The proteins may be further purified, for example, by affinity resin chromatography. Alternatively, proteins can be transported into the culture media and isolated therein. Cells may be removed horn the culture and the culture supernatant being filtered and concentrated for further purification of the proteins produced. The expressed polypeptides can be further isolated and identified using commonly known methods such as polyacrylamide gel electrophoresis (PAGE) and Western blot assay. in one aspect of the invention, masked cytokine production is conducted in large quantity by a fermentation process. Various large-scale fed-batch fermentation procedures are available for production of recombinantproteins. Large-scale fermentations have at least 1000 liters of capacity, and in certain embodiments, about 1,000 to 100,000 liters of capacity. These fermenters use agitator impellers to distribute oxygen and nutrients, especially glucose. Small scale fermentation refers generally to fermentation in a fermenter that is no more than approximately 100 liters in volumetric capacity, and can range horn about 1 liter to about 100 liters.In a fermentation process, induction of protein expression is typically initiated after the cells have been grown under suitable conditions to a desired density, e.g., an OD550 of about 180-220, at which stage the cells are in the early stationary phase. A variety of inducers may be used, according to the vector construct employed, as is known in the art and described above. Ceils may be grown for shorter periods prior to induction. Cells are usually induced for about 12-50 hours, although longer or shorter induction time may be used.To improve the production yield and quality of the polypeptides of the invention, various fermentation conditions can be modified. For example, to improve the proper assembly and folding of, for example, secreted antibody polypeptides, additional vectors overexpressing chaperone proteins, such as Dsb proteins (DsbA, DsbB, DsbC, DsbD and or DsbG) or FkpA (a peptidylprolyl cis,trans-isomera$e with chaperone activity) can be used to co-transform the host prokaryotic cells The chaperone proteins have been demonstrated to facilitate the proper folding and solubility of heterologous proteins produced in bacterial host cells Chen et al. (1999) J. Biol. Chem. 274:19601-19605; Georgiou et ak, U.S. Pat. No. 6,083,715; Georgiouetak, U.S Pat. No. 6,027,888; Bothmann andP!uckthun (2000) J. Biol. Chem. 275:17100-171 5; Ramm and Pluckthun (2000) j. Biol. Chem. 275:17106-17113; Arie et ak (2001) Mol. Microbiol. 39:199- 210To minimize proteolysis of expressed heterologous proteins (especially those that are proteolytically sensitive), certain host strains deficient for proteolytic enzymes can be used for the present invention. For example, host cell strains may be modified to effect genetic mutation(s) in the genes encoding known bacterial proteases such as Protease IP, OrnpT, DegP, Tsp, Protease L Protease Mi, Protease V, Protease VI and combinations thereof. Some E. coli protease-deficient strains are available and described in, for example, Joly et ak (1998), supra; Georgiou et ak, U.S. Pat. No.5,264,365 Georgiou et alt, U.S. Pat. No. 5, 508, 192; Kara etak, Microbial Drug Resistance, 2:63-72 (1996).In some embodiments, E. coli strains deficient for proteolytic enzymes and transformed with plasmids overexpressing one or more chaperone proteins are used as host cells in the expression system of the invention. c Masked Cytokine Purificationin some embodiments, the masked cytokine produced herein is further purified to obtain preparations that are substantially homogeneous for further assa s and uses. Standard protein purification methods known in the art can be employed. The following procedures are exemplary of suitable purification procedures: fractionation on immunoaffinity or ion-exchange columns, ethanol precipitation, reverse phase HPLC, chromatography on silica or on a cation-exchange resin such as DEAE, chromatofocusing, SDS-PAGE, ammonium sul ate precipitation, and gel filtration using, for example, Sephadex G-75.In some embodiments, Protein A immobilized on a solid phase is used for immunoaffinity purification of the masked cytokines of the invention. Protein A is a 41 kD cell wall protein from Staphylococcus aureas which binds with a high affinity to the Fc region of antibodies. Lindmark et al (1983) I Immunol. Meth. 62:1-33. The solid phase to which Protein A is immobilized can be a column comprising a glass or silica surface, or a controlled pore glass column or a silicic acid column. In some applications, the column is coated with a reagent, such as glycerol, to possibly prevent nonspecific adherence of contaminants.As the first step of purification, a preparation derived from the ceil culture as described above can be applied onto a Protein A immobilized solid phase to allow specific binding of the masked cytokine of interest to Protein A. The solid phase would then be washed to remove contaminants non- specifically bound to the solid phase. Finally, the masked cytokine of interest is recovered from the solid phase by elution.Other methods of purification that provide for high affinity binding to a component of the masked cytokine can be employed in accordance with standard protein purification methods known in the art.2. Generating Masked Cytokines Using Eukaryotic Host CellsA vector for use in a eukaryotic host cell generally includes one or more of the following non-limiting components: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. a. Signal Sequence ComponentA vector for use in a eukar otic host cell may also contain a signal sequence or other polypeptide having a specific cleavage site at the N-temiinus of the mature protein or polypeptide of interest. The heterologous signal sequence selected may be one that is recognized and processed (i.e., cleaved by a signal peptidase) by die host cell. In mammalian cell expression, mammalian signal sequences as well as viral secretory' leaders, for example, the herpes simplex gD signal, are available.The DNA for such a precursor region is ligated in reading frame to DNA encoding the masked cytokine b. Origin of ReplicationGenerally, an origin of replication component is not needed for mammalian expression vectors. For example, the SV40 origin may typically be used only because it contains the early promoter. c. Selection Gene ComponentExpression and cloning vectors may contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, where relevant, or (c) supply critical nutrients not available from complex media.One example of a selection scheme utilizes a drug to arrest growth of a host cell. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection regimen. Examples of such dominant selection use the drugs neom cin, mycopheno!ic acid and bygromycin.Another example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the masked cytokine encoding nucleic acid, such as DHFR, thymidine kinase, metallothionein-I and -TI, primate metallothionein genes, adenosine deaminase, ornithine decarboxylase, etc.For example, in some embodiments, cells transformed with rite DHFR selection gene are first identified by culturing ail of the transformants in a culture medium that contains methotrexate (Mtx), a competitive antagonist of DHFR. In some embodiments, an appropriate host cell when wild-type DHFR is employed is the Chinese hamster ovary' (CHO) ceil line deficient in DHFR activity (e.g., ATCC CRL- 9096).Alternatively, host cells (particularly wild-type hosts that contain endogenous DHFR) transformed or co- transfonned with DNA sequences encoding a masked cytokine, wild-type DHFR protein, and another selectable marker such as aminoglycoside 3 -phosphotransferase (APH) can be selected by cell growth in medium containing a selection agent for the selectable marker such as an aminogiycosidic antibiotic, e.g., kanamydn, neomycin, or G418. See U.S. Pat. No. 4,965, 199. Host cells may include NS0, including cell lines deficient in glutamine synthetase (GS) Methods for the use of GS as a selectable marker for mammalian cells are described in U.S. Pat. No. 5,122,464 and U.S. Pat. No. 5,891,693. d. Promoter ComponentExpression and cloning vectors usually contain a promoter that is recognized by the host organism and is operably linked to nucleic acid encoding a masked cytokine of interest, which can be any masked cytokine described herein. Promoter sequences are known for eukaryotes. For example, virtually all eukaryotic genes have an AT-rich region located approximately 25 to 30 bases upstream front the site where transcription isinitiated. Another sequence found 70 to 80 bases upstream from the shirt of transcription of many genes is a CNCAAT region where N may be any nucleotide. At the 3' end of most eukaryotic genes is an A AT AAA sequence that may be the signal for addition of the poly A tail to the 3' end of the coding sequence in certain embodiments, any or all of these sequences may be suitably inserted iirto eukary otic expression vectors.Transcritihon from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepahtis-B vims and Simian Vims 40 (S V40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, from heat-shock promoters, provided such promoters are compatible with the host cell systems.The early and late promoters of tie SV40 vims are conveniently obtained as an SV40 restrichon fragment that also contains the SV40 viral origin of replication. The immediate early promoter of the human cytomegalovirus is conveniently obtained as a Hindlll E restriction fragment. A sy tem for expressing DNA in mammalian hosts using the bovine papilloma virus as a vector is disclosed in U.S. Pat. No. 4,419,446. A modification of tins s stem is described inU.S. Pat. No. 4,601,978. See also Reyes et ah, Nature 297:598- 601 (1982), describing expression of human [3 -interferon cDNA in murine cells under the control of a thymidine kinase promoter from herpes simplex virus. Alternatively, the Rous Sarcoma Virus long terminal repeat can be used as the promoter e. Enhancer Element ComponentTranscription of DNA encoding a masked cytokine of this invention by higher eukaryotes is often increased by inserting an enhancer sequence into the vector. Many enhancer sequences are now known from mammalian genes (globia elastase, albumin, a-fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the human cytomegalovirus early promoter enhancer, the murine cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. See also Yaniv, Nature 297:17-18 (1982) (describing enhancer elements for activation of eukaryotic promoters). The enhancer may be spliced into the vector at a position 5' or 3' to the masked cytokine-encoding sequence, but is generally located at a site 5' from the promoter. f. Transcription Termination ComponentExpression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription and for stabilizing she mRNA. Such sequences are commonly available from the 5' and, occasionally 3’, untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions containnucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding a masked cytokine. One useful transcription termination component is the bovine growth hormone poiyadeny lation region. See W094 / 11026 and the expression vector disclosed therein. g. Selection and Transformation of Host CellsSuitable host cells for cloning or expressing the DNA in the vectors herein include higher eukaryote cells described herein, including vertebrate host cells. Propagation of vertebrate cells in culture (tissue culture) lias become a routine procedure. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et ah, J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells / -DHFR (CHO, Urlaub et ah, Proc. Natl. Acad. Sci. USA 77:4216 (1980)); murine sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BEL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); murine mammary tumor (MMT 060562, ATCC CCL51); TRI ceils (Mather et ah, Annals N.Y. Acad. Sci. 383 :44-68 ( 1982)); MRC 5 cells; FS4 cells; and a human hepatoma line (Hep G2).Host cells are transformed with the above-described-expression or cloning vectors for masked cytokine production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. h. Culturing Host CellsThe host cells used to produce masked cytokines of this invention may be cultured in a variety of media. Commercially available media such as Ham’s F10 (Sigma), Minimal Essential Medium ((MEM), Sigma), RPMI-1640 (Sigma), and Dulbecco’s Modified Eagle’s Medium ((DMEM), Sigma) are suitable for culturing the host cells. In addition, any of the media described in Ham et ah, Meth. Enz. 58:44 (1979), Barnes et ah, Anal. Biochem. 102:255 (1980), U.S. Pat No. 4,767,704; 4,657,866;A, 921,162\ 4,560,655; or 5,122,469; WO 90 / 03430; WO 87 / 00195; or U.S. Pat. Re. 30,985 may be used as culture media for the host cells. Any of these media may be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as GENTAMYCIN™ drug), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other supplements may also be included at appropriate concentrations that would be known to those skilled in the art. The culture conditions, such as temperature, pH, and the like, are thosepreviously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan. i. Purification of Masked CytokinesWhen using recombinant techniques, the masked cytokines can be produced mtracellularly, or directly secreted into the medium if the masked cytokine is produced iritiacellulariy, as a first step, the particulate debris, either host ceils or lysed fragments, may be removed, for example, by centrifugation or uitrafiltration. Where the masked cytokine is secreted into the medium, supernatants from such expression systems may be first concentrated using a commercially available protein concentration filter, for example, an Amicon or Miliipore Peliicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteoly is, and antibiotics may be included to prevent the growth of adventitious contaminants.The masked cytokine composition prepared from the cells can be purified using, for example, hydroxylapatiie chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a convenient technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain, if any, that is present in the masked cytokine. Protein A can be used to purify antibodies that are based on human IgG!, TgG2, or IgG4 heavy chains (landmark et ak, J. Immunol. Methods 62:1-13 ( 1983)). Protein G is recommended for all murine isotypes and for human y3 (Guss et ak, EMBO J. 5:15671575 (1986)). The matrix to which the affinity ligand is attached may be agarose, but other matrices are available. Mechanically stable matrices such as controlled pore giass or poly (styrenedivmyilberizene allow' for faster flow' rates and shorter processing times than can be achieved with agarose. Where the masked cytokine comprises a CH3 domain, the Bakerbond ABX™ resin (J. T. Baker, Phillipsburg, N. J.) is useful for purification. Other techniques for protein purification such as fractionahon on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSE™ chromatography on an anion or cation exchange resin (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available depending on the masked cytokine to be recovered.Following any preliminary purification step(s), the mixture comprising the masked cytokine of interest and contaminants may be subjected to further purification, for example, by low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5-4.5, performed at low salt concentrations (e.g., from about 0-0.25M salt). in general, various methodologies for preparing masked cytokines for use in research testing, and clinical use are well-established in the art, consistent with the above-described methodologies and / or as deemedappropriate by one skilled in the art for a particular masked cytokine of interest.5, COMPOSITIONS In some aspects, also provided herein are compositions comprising any of the IL-12 masked cytokines described herein. In some embodiments, tire composition comprises any of tire exemplary embodiments of masked IL-12 cytokine described herein. In some embodiments, the composition comprises a dimer of any of tire masked IL-12 cytokines described herein in some embodiments, tire composition is a pharmaceutical composition. In some embodiments, the composition comprises a masked IL-12 cytokine and further comprises one or more of the components as described in detail below. For example, in some embodiments, the composition comprises one or more pharmaceutically acceptable carriers, excipients, stabilizers, buffers, preservatives, tonicity agents, non-ionic surfactants or detergents, or other therapeutic agents or active compounds, or combinations thereof. The various embodiments of the composition are sometimes referred to herein as formulations.Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional pharmaceutically acceptable earners, excipients or stabilizers (Remington: Tire Science and Practice of Pharmacy, 20th Ed., Lippmcott Williams & Wiklins, Pub., Getinaro Ed., Philadelphia, Pa. 2000). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers, antioxidants including ascorbic acid, methionine, Vitamin E, sodium metabisulfite; preservatives, isotonicifiers, stabilizers, metal complexes (e.g. Zn-protein complexes); chelating agents such as EDTA and / or non-ionic surfactants.Buffers can be used to control the pH in a range which optimizes the therapeutic effectiveness, especially if stability is pH dependent. Buffers can be present at concentrations ranging from about 50 inM to about 250 mM. Suitable buffering agents for use with the present invention include both organic and inorganic acids and salts thereof. For example, citrate, phosphate, succinate, tartrate, fumarate, gluconate, oxalate, iactate, acetate. Additionally, buffers may be comprised of histidine and trimethy!amine sails such as Tris. Preservatives can be added to prevent microbial growth, and are typically present in a range from about 0.2%-1.0% (w / v). Examples of suitable preservatives commonly used with therapeutics include octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium halides (e.g., chloride, bromide, iodide), benzethonimn chloride; thimerosal, phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol, 3-pentanoi, m- cresol, o- cresoi, p-cresol, methyl p-hydroxy benzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p- hydroxybenzoate, 2-phenylethanoi, ethanol, chlorobutanol, thiomerosal, bronopol, benzoic acid, imidurea, chiorohexidine, sodium dehydroacetate, cMorocresol, ethyl p-hydroxybenzoate, and chlorphenesine (3p-chlorphenoxypropane-1 ,2- diol).Tonicity agents, sometimes known as “stabilizers” can be present to adjust or maintain the tonicity of liquid in a composition. When used with large, charged biomolecules such as proteins and antibodies, they are often termed “stabilizers” because they can interact with the charged groups of the amino acid side chains, thereby lessening the potential for inter and intra-molecular interactions.Tonicity agents can be present in any amount between about 0.1% to about 25% by weight or between about 3 to about 5% by weight, taking into account the relative amounts of the other ingredients. In some embodiments, tonicity agents include polyhydric sugar alcohols, trihydric or higher sugar alcohols, such as glycerin, erythiitol, arabitol, xylitol, sorbitol and mannitol.Additional excipients include agents which can serve as one or more of the following: (1) bulking agents, (2) solubility enhancers, (3) stabilizers and (4) and agents preventing denaturation or adherence to the container wall. Such excipients include: polyhydric sugar alcohols (enumerated above); amino acids such as alanine, glycine, glutamine, asparagine, histidine, arginine, ly sine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactilol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as urea, glutathione, thioctlc acid, sodium thioglycolate, thioglycerol, a-monothioglycerol and sodium thio sulfate; low molecular weight proteins such as human serum albumin, bovine serum albumin, gelatin or other immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides (e.g., xylose, mannose, fructose, glucose; disaccharides (e.g., lactose, maltose, sucrose); trisaccharides such as raffinose; and polysaccharides such as dextrin or dextranNon-ionic surfactants or detergents (also know n as “wetting agents”) can be present to help solubilize the therapeutic agent as well as to protect the therapeutic protein against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stress without causing denaturation of the active therapeutic protein or antibody. Non-ionic surfactants are present in a range of about 0.05 rng / ml to about 1.0 g / ml or about 0.07 mg / mi to about 0.2 mg / ml. In some embodiments, non-ionic surfactants are present in a range of about 0.001% to about 0.1% w / v or about 0.01% to about 0.1% w / v or about 0.01% to about 0.025% w v.Suitable non-ionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), polyoxamers (184, 188, etc ), PLURONiC® polyols, TRITON®, polyoxyethylene soibitan monoethers (TWEEN®-20, TWEEN®-80, etc.), lauroroacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, sucrose fatty acid ester, methyl celluose and carboxymethyi cellulose. Anionic detergents that can be used include sodium lauiyl sulfate, dioctyie sodium sulfosuccinate and dioctylsodium sulfonate. Cationic detergents include benzalkonuun chloride or benzethonium chloride.In order for the formulations to be used for in vivo administration, they must be sterile. The formulation may be rendered sterile by filtration through sterile filtration membranes. The therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.The route of administration is in accordance with known and accepted methods, such as by single or multiple bolus or infusion over a long period of time in a suitable manner, e.g., injection or infusion by subcutaneous, intravenous, intraperitoncal, intramuscular, intraarterial, intralesionai or intraarticular routes, topical administration, inhalation or by sustained release or extended-release means.Any of the masked EL- 12 cytokines described herein can be used alone or in combination with other therapeutic agents such is in tire methods described herein. The term “in combination with"encompasses two or more therapeutic agents (e.g., a masked 3L-12 cytokine and a therapeutic agent) that are included in the same or separate formulations. In some embodiments, “in combination with” refers to “simultaneous” administration, in which case administration of the masked 1L-12 cytokine of the invention occurs simultaneously to the administra tion of the one or more additional therapeutic agents (e g , at the same time or within one hour between administration (s) of the masked 1L-12 cytokine and administration of the one or more additional therapeutic agents). In some embodiments, “in combination with” refers to sequential administration, in which case administration of the masked 1L-12 cytokine of the invention occurs prior to and / or following, administration of the one or more additional therapeutic agents (e.g., greater than one hour between administration (s) of the masked IL-12 cytokine and administration of the one or more additional therapeutic agents). Agents contemplated herein include, but are not limited to, a cytotoxic agent, a cytokine, an agent targeting an immune checkpoint molecule, an agent targeting an immune stimulatory molecule, a growth inhibitory' agent, an immune stimulatory' agent, an anti-inflammatory agent, or an anti- cancer agent.The formulation herein may also contain more than one active compound as necessary' for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine, agent targeting an immune checkpoint molecule or stimulatory molecule, growth inhibitory' agent, an immune stimulatory agent, an anti-inflammatory agent, or an anti-cancer agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.The formulation may be presented in any suitable state, such as a liquid formulation, a solid state (lyophilized) formulation, or a frozen formulation. Approaches for preparing each of these types of formulations for therapeutic use are well known in the art.6. METHODS OF TREATMENTProvided herein are methods for treating or preventing a disease in a subject comprising administering to the subject an effective amount of any masked TL-12 cytokine described herein or compositions thereof in some embodiments, methods are provided for treating or preventing a disease in a subject comprising administering to the subject any composition described herein. In some embodiments, tire subject (e.g., a human patient) has been diagnosed with cancer or is at risk of developing such a disorder. In some embodiments, methods are provided for treating or preventing disease in a subject comprising administering to the subject an effective amount of any masked IL-12 cytokine described herein or compositions thereof, wherein the masked IL-12 cytokine is activated upon cleavage by an enzyme. In some embodiments, the masked IL-12. cytokine is activated at a tumor microenvironment. The masked IL- 12 cytokine is therapeutically active after it has cleaved. Thus, in some embodiments, the active agent is the cleavage product.For the prevention or treatment of disease, the appropriate dosage of an active agent will depend on the type of disease to be treated, as defined herein, the severity and course of the disease, whether the agent is administered for preventive or therapeutic purposes, previous therapy, the subject’s clinical history and response to the agent, and the discretion of the atending physician. The agent is suitably administered to the subject at one time or over a series of treatments.In some embodiments of the methods described herein, an interval between administrations of a masked IL-12 cytokine described herein is about one week or longer. In some embodiments of Hie methods described herein, an interval betw een administrations of a masked IL-12 cytokine described herein is about two day s or longer, about three days or longer, about four day s or longer, about five day s or longer, or about six days or longer. In some embodiments of the methods described herein, an interval between administrations of a masked IL-12 cytokine described herein is about one week or longer, about two weeks or longer, about three weeks or longer, or about four weeks or longer. In some embodiments of the methods described herein, an interval between administrations of a masked IL-12 cytokine described herein is about one month or longer, about two months or longer, or about three months or longer. As used herein, an interval between administrations refers to the time period between one administration of the masked IL-12 cytokine and the next administration of the masked IL-12 cytokine. As used herein an interval of about one month includes four weeks. In some embodiments, the treatment includes multiple administrations of the masked IL-12 cytokine, wherein the interval between administrations may vaiy. For example, in some embodiments, the interval between the first administration and Ore second administration is about one week, and the intervals between the subsequent administrations are about two weeks. In some embodiments, the interval between the first administration and the second administration is about two days, three days, fourdays, or five days, or six da s, and the intervals between the subsequent administrations are about one week.In some embodiments, the masked IL-12 cytokine is administered on multiple occasions over a period of time. The dosage that is administered to the subject on multiple occasions can, in some embodiments, be the same dosage for each administration, or, in some embodiments, the masked cy tokine can be administered to the subject at two or more different dosages. For example, in some embodiments, a masked IL-12 cytokine is initially administered at one dosage on one or more occasions and is later administered at a second dosage on one or more occasions beginning at a later time point.In some embodiments, a masked IL-12 polypeptide described herein is administered at aflat dose. In some embodiments, a masked IL-12 polypeptide described herein is administered to a subject at a dosage from about 25 mg to about 500 mg per dose. In some embodiments, the masked IL-12 polypeptide is administered to a subject at a dosage of about 25rag to about 50mg, about 50mg to about 75mg, about 75mg to about lOOmg, about lOOmg to about 125mg, about 125mg to about 150mg, about 150mg to about 175mg, about 175mg to about 200mg, about 200mg to about 225mg, about 225mg to about 25Qmg, about 250mg to about 275mg, about 275mg to about 300mg, about 300mg to about 325mg, about 325mg to about 350mg, about 350mg to about 375mg, about 375mg to about 400mg, about 400mg to about 425 mg, about 425mt to about 450mg, about 450mg, to about 475mg, or about 475mg to about 500mg per dose. in some embodiments, a masked IL-12 polypeptide described herein is administered to a subject at a dosage based on the subject’s weight or body surface area (BSA). Depending on the type and severity of the disease, about 1 jig / kg to 15 mg / kg (e.g. 0. 1 rag kg-lOmg / kg) of masked IL-12 polypeptide can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. One typical daily dosage might range from about 1 pg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary' dosage of the masked IL-12 polypeptide would be in the range from about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg kg or 10 mg / g (or any combination thereof) may be administered to the patient. In some embodiments, a masked IL-12 polypeptide described herein is administered to a subject at a dosage from about 0.1 mg / kg to about 10 mg / kg or about 1.0 mg / kg to about 10 mg / kg. In some embodiments, a masked IL-12 polypeptide described herein is administered to a subject at a dosage of about any of 0.1 mg / kg, 0.5 mg / kg, 1.0 ing / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg, 'kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg kg, 7.0 mgkg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, or 10.0 mg / kg In some embodiments, a masked IL-12 polypeptide described herein is administered to a subject at a dosage of about or at least about O. i mg / kg, about or at least about 0.5 mg / kg, about or at least about 1.0 mg / kg, about or at least about 1.5 mg / kg, about or at least about 2.0 mg / kg, about or at least about 2 5 mg / kg, about or at least about 3.0 mg / kg, about or at least about 3.5 mg kg, about or at least about4.0 mg / kg, about or at least about 4.5 mg / kg, about or at least about 5.0 mg / kg, about or at least about 5.5 mg / kg, about or at least about 6.0 mg / kg, about or at least about 6.5 mg / kg, about or at least about 7.0 mg / kg, about or at least about 7.5 mg / kg, about or at least about 8.0 rug / kg, about or at least about 8.5 mg / kg, about or at least about 9.0 mg / kg, about or at least about 9.5 mg / kg, about or at least about 10.0 mg / kg, about or at least about 15.0 mg / kg, about or at least about 20mg / kg, about or at least about 30mg / kg, about or at least about 40mg / kg, about or at least about 50mg / kg, about or at least about 60mg / kg, about or at least about 70mg / kg, about or at least about 80mg / kg, about or at least about 90mg / kg, or about or at least about lQ0mg / kg. Any of the dosing frequencies described above may be used.A method of treatment contemplated herein is the treatment of a disorder or disease such as cancer with any of the masked IL- 12 cytokines or compositions described herein. Disorders or di eases that are treatable with the formulations of this present invention include leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma, lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma) or testicular cancer. in some embodiments, provided herein is a method of treatment or prevention of a cancer by administration of any masked 1L-12 cytokines or compositions described herein In some embodiments, provided herein is a method of treatment or prevention of a cancer by administration of any IL-12 masked cytokine or composition described herein in combination with an anticancer agent. The anti-cancer agent can be any agent capable of reducing cancer growth, interfering with cancer cell replication, directly or indirectly killing cancer cells, reducing metastasis, reducing tumor blood supply, or reducing cell survival. In some embodiments, the anti-cancer agent is selected from the group consisting of a PD-1 inhibitor, an EGFR inhibitor, a HER2 inhibitor , a VEGFR inhibitor, a CTLA-4 inhibitor, a BTLA inhibitor, a B7H4 inhibitor, a B7H3 inhibitor, a CSFTR inhibitor, an HVEM inhibitor, a CD27 inhibitor, a KIR inhibitor, an NKG2 A inhibitor, an NKG2D agonist, a TWEAK inhibitor, an ALK inhibitor, a CD52 targeting antibody, a CCR4 targeting antibody, a PD-L1 inhibitor, a KIT inhibitor, a PDGFR inhibitor, a BAFF inhibitor, an HD AC inhibitor, a VEGF ligand inhibitor, a CD19 targeting molecule, a FOFR1 targeting molecule, a DFF3 targeting molecule, a DKK1 targeting molecule, a MUC1 targeting molecule, a MUG 16 targeting molecule, a PSMA targeting molecule, an MSFN targeting molecule, an NY-ESO-1 targeting molecule, a B7H3 targeting molecule, a B7H4 targeting molecule, a BCMA targeting molecule, a CD29 targeting molecule, a CD151targeting molecule, a CD 123 targeting molecule, a CD33 targeting molecule, a CD37 targeting molecule, a CDH19 targeting molecule, a CEA targeting molecule, a Claudin 18.2 targeting molecule, a CFEC12A targeting molecule, an EGFR VIII targeting molecule, an EPGAM targeting molecule, an EPHA2 targeting molecule, an FCRH5 targeting molecule, an FLT3 targeting molecule, a GD2 targeting molecule, a glypican 3 targeting molecule, a gpA33 targeting molecule, a GPRC5D targeting molecule, an IL-123R targeting molecule, an IL-1RAP targeting molecule, a MCSP targeting molecule, a RON targeting molecule, a ROR1 targeting molecule, a STEAP2 targeting molecule, a TfR targetingmolecule, a CD166 targeting molecule, a TPBG targeting molecule, a TROP2 targeting molecule, a proteasome inhibitor, an ABE inhibitor, a CD30 inhibitor, a FL.T3 inhibitor, a MET inhibitor, a RET inhibitor, an IL- 1(3 inhibitor, a MEK inhibitor, a ROS1 inhibitor, a BRAE inhibitor, a CD38 inhibitor, a RANKE inhibitor, a B4GALNT1 inhibitor, a 8LAMF7 inhibitor, anIDH2 inhibitor, anmTOR inhibitor, a CD20 targeting antibody, a BTK inhibitor, a P13K inhibitor, a FLT3 inhibitor, a PARP inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, an EGFR inhibitor, a RAF inhibitor, a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, an lL-6 inhibitor, a 1L-17 inhibitor, a Smoothened inhibitor, an IL-6R inhibitor, a BCL2 inhibitor, a PTCH inhibitor, a PIGF inhibitor, a TGFB inhibitor, a CD28 agonist, a CD3 agonist, CD40 agonist, a GITR agonist, a 0X40 agonist, a VISTA agonist, a CD137 agonist, a LAG3 inhibitor, a TIMS inhibitor, a TIG1T inhibitor, and an IL-12R inhibitor.In some embodiments, provided herein is a method of treatme nt or prevention of a cancer by administration of any masked 11,-12 cytoki ne described herein in combination with an anti-inflammatory agent. The antiinflammatory agent can be any agent capable of preventing, counteracting, inhibiting, or otherwise reducing inflammation. in some embodiments, the anti-inflammatory agent is a cyclooxygenase (COX) inhibitor. The COX inhibitor can be any agent that inhibits the activity of COX-1 and / or COX-2 in some embodiments, the COX inhibitor selectively inhibits COX-1 (i.e., the COX inhibitor inhibits the activity of COX-1 more than it inhibits the activity of COX-2). In some embodiments, the COX inhibitor selectively inhibits COX-2 (i.e., the COX inhibitor inhibits the activity of COX-2 more than it inhibits the activity of COX-1). In some embodiments, the COX inhibitor inhibits both COX-1 and COX-2In some embodiments, (he COX inhibitor is a selective COX- 1 inhibitor and is selected from the group consisting of SC-560, FR122047, P6, mofezolac, TFAP, flurbiprofen, and ketoprofen In some embodiments, the COX inhibitor is a selective COX-2 inhibitor and is selected from the group consisting of celecoxib, rofecoxib, mdoxicam, piroxicam, deracoxib, parecoxib, valdecoxib, etoricoxib, a chro ene derivative, a chroman derivative, N-(2-cyclohexyIoxynitrophenyl) methane sulfonamide, parecoxib, iumiracoxih, RS 57067, T-6I4, BMS-347070, JTE-522, S-2474, SVT- 2016, CT-3, ABT-963, SC-58125, mmesulide, flosulide, NS-398, L- 745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS- 34555, S-33516, diclofenac, mefenamic acid, and SD-8381. In some embodiments, the COX inhibitor is selected from the group consisting of ibuprofen, naproxen, ke torolac, indome thacin, aspirin, naproxen, tolmetin, piroxicam, and meclofenamate. In some embodiments, the COX inhibitor is selected from the group consisting of SC-560, FR122047, P6, mofezolac, TFAP, flurbiprofen, ketoprofen, celecoxib, rofecoxib, meioxicam, piroxicam, deracoxib, parecoxib, valdecoxib, etoricoxib, a chromene derivative, a chroman derivative, N-(2-cyclohexyloxynitrophenyl) methane sulfonamide, parecoxib, lumiracoxib, RS 57067, T-614, BMS-347070, JTE-522, S-2474, SVT- 2016, CT-3, ABT-963. SC-58125 mmesulide, flosulide, NS-398, L- 745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS- 34555, S-33516, diclofenac, meferamic acid, SD-838L ibuprofen, naproxen, ketorolac, indomethacin, aspirin, naproxen, tolmetin, piroxicam, and ineclofenainate.In some embodiments, the ami -inflammatory agent is an NF-KB inhibitor. The NF-KB inhibitor can be any agent that inhibits the activity of the NF-KB pathway. In some embodiments, the NF-KB inhibitor is selected from the group consisting of an IKK complex inhibitor, an IKB degradation inhibitor, an NF-KB nuclear translocation inhibitor, a p65 acetylation inhibitor, an NF-KB DNA binding inhibitor, an NF-KB transactivation inhibitor, and a p53 induction inhibitor.In some embodiments, the IKK complex inhibitor is selected from the group consisting of TPCA-1, NF- KB Activation Inhibitor VI (BOT-64), BMS-345541, atnlexanox, SC-534 (GK-01140), IMD-0354, and IKK- 36. In some embodiments, the IKB degradation inhibitor is selected from the group consisting of BAY - 31-7082, MG-115, MG- 332, lactacystin, epoxotnicin, parthenolide, carfiizomib, and MLN-4924 (pevonedistat). in some embodiments, the NF-KB nuclear translocation inhibitor is selected from the group consisting of JSFI-23 and rolipram. In some embodiments, the p65 acetylation inhibitor is selected from the group consisting of gallic acid and anacardic acid. In some embodiments, the NF-kB DNA binding inhibitor is selected from the group consisting of GYY-4137, p-XSC, CV-3988, and prostaglandin E2 (PGE2). In some embodiments, the NF-kB transactivation inhibitor is selected from the group consisting of LY- 294002, wortmaimin, and mesalamine. In some embodiments, the p53 induction inhibitor is selected from the group consisting of quinacrine and flavopiridol. In some embodiments, the NF-KB inhibitor is selected from the group consisting of TPCA-1, NF-KB Activation Inhibitor VI (BOT- 64), BMS-345541, amlexanox, SC-514 (GK-01140), TMD-0354, IKK- 16, BAY-11-7082, MG-115, MG- 332, lactacystin, epoxomicin, parthenolide, carfiizomib, MLN-4924 (pevonedistat), JSH-23 rolipram, gallic acid, anacardic acid, GYY-4137, p-XSC, CV-3988, prostaglandin E2 (PGE2), LY-294G02, wortmannia mesalamine, quinacrine, and flavopiridol. in some embodiments, provided herein is a method of treatment or prevention of a cancer by administration of any masked IL-12 cytokine or composition described herein in combination with an anticancer therapeutic protein. The anti-cancer therapeutic protein can be any therapeutic protein capable of reducing cancer grow th, interfering with cancer cell replication, directly or indirectly killing cancer cells, reducing metastasis, reducing tumor blood supply, or reducing cell survival. Exemplar}' anti-cancer therapeutic proteins may come in the form of an antibody or fragment thereof, an antibody derivative, a bispecific antibody, a chimeric antigen receptor (CAR) T cell, a fusion protein, or a bispecific T-cell engager (BiTE). In some embodiments, provided herein is a method of treatment or prevention of a cancer by administration of any masked IL-2 cytokine or composition described herein in combination with CAR-NK (Natural Killer) cells.7. ARTICLES OF MANUFACTURE OR KITS in another aspect, art article of manufacture or kit is provided which comprises arty masked IL-12 cytokine described herein. The article of manufacture or kit may further comprise instructions for use of the cytokines in the methods of the invention. Thus, in certain embodiments, the article of manufacture or kit comprises instructions for the use of a masked cytokine in methods for treating or preventing a disorder (e.g., a cancer) in an individual comprising administering to the individual an effective amount of a masked cytokine. For example, in certain embodiments, the article of manufacture or kit comprises instructions for the use of a masked IL-12 polypeptide in methods for treating or preventing a disorder (e.g., a cancer) in an individual comprising administering to the individual an effective amount of a masked IL-12 polypeptide. In certain embodiments, the individual is a human. In some embodiments, the individual lias a disease selected from the group consisting of include leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma, lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer or testicular cancer.The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes), test tubes, and intravenous (IV) bags. The container may be formed from a variety of materials such as glass or plastic. The container holds the formulation. In some embodiments, the formulation is a iyophilized formulation. In some embodiments, the formulation is a frozen formulation. In some embodiments, the formulation is a liquid formulation.The article of manufacture or kit may further comprise a label or a package insert, which is on or associated wish the container, may indicate directions for reconstitution and / or use of the formulation The label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous, or other modes of administration for treating or preventing a disorder (e.g., a cancer) in an individual. The container holding foe formulation may be a single-use vial or a multi-use vial, which allows for repeat administrations of the reconstituted formulation. The article of manufacture or kit may further comprise a second container comprising a suitable diluent. The article of manufacture or kit may further include other materials desirable from a commercial, therapeutic, and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.In a specific embodiment, the present invention provides kits for a single dose-administration unit. Such kits comprise a container of an aqueous formulation of therapeutic cytokine, including both single or multi-chambered pre-filled syringes. Exemplary pre-filled syringes are available from Veter GmbH, Ravensburg, Germany.The article of manufacture or kit herein optionally further comprises a container comprising a second medicament, wherein die masked cytokine is a first medicament, and which article or kit further comprises instructions on the label or package insert for treating the subject with the second medicament, in an effective amountIn another embodiment, provided herein is an article of manufacture or kit comprising the formulations described herein for administration in an auto-injector device. An auto-injector can be described as an injection device that upon activation, will deliver its contents without additional necessary action from the patient or administrator. They are particularly suited for self-medication of therapeutic formulations when the delivery rate must be constant and the time of delivery is greater than a few moments.8. DEFINITIONSUnless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. it is to be understood that this invention is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that Use terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a," “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “an TL-12 polypeptide” optionally includes a combination of two or more such polypeptides, and the like.The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.It is understood that aspects and embodiments of die invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.As used herein, the term “and / or” refers to any one of the items, any combination of the items, or all of the items with which the term is associated. For instance, the phrase “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; Band C; A and B or C; B and A or C; C and A or B; A (alone); B (alone); and C (alone).The term “antibody” includes polyclonal antibodies, monoclonal antibodies (including Ml length antibodies which have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules, as well as antibody fragments (e.g., Fab, F(ab’)2, and Fv). The term “immunoglobulin” (Ig) is used interchangeably with “antibody” herein.The term “diabodies”refers to small antibody fragments with two antigen-binding sites, which comprise a heavy drain variable (VH) domain connected to a light drain variable (VL) domain in tire same polypeptide chain (VH-VL)The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) drains and two identical heavy (H) drains. Art IgM antibody consists of 5 of the basic heterotetramer units along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2.-5 of the basic 4-chain units which can polymerize to form polyvalent assemblages m combination with the 1 chain. In the case oflgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while tire two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also Iras regularly spaced intrachain disulfide bridges. Each H chain has at the N-temunus, a variable domain ( VH) followed by three constant domains (CH) for each of the a and y chains and four CH domains for p and s isotypes. Each L chain lias at the N-terminus, a variable domain (VL) followed by a constant domain at its other end. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CHI). Particular amino acid residues are belie ved to form an interface between the light drain and heav drain variable domains. The pairing of a VH and VL together forms a single antigen- binding site. For the structure and properties of the different classes of antibodies, see e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on tire amino acid sequence of the constant domain of their heavy drains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, TgE, TgG and IgM, having heavy chains designated a, 8, e, y and p, respectively. The y and a classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: IgGI, IgG2, XgG3, IgG4, IgAI and IgA2 IgGl antibodies can exist in multiple pol morphic variants termed allotypes (reviewed in Jefferis and Leftaoc 2009. niAbs Vol 1 Issue 4 1-7) any of which are suitable for use in the invention. Common allotypic variants in human populations arethose designated by the leters a£n,z.An “isolated” antibody is one that has been identified separated and / or recovered from a component of its production environment (e.g., naturally or reeombinantly). in some embodiments, the isolated polypeptide is free of association wi th all other components from its produc tion environment. Contaminant components of i s production environment, such as that resulting from recombinant transfected celis, are materials that would typically interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the polypeptide is purified: (1) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to .greater than 99% by weight; (1) to a degree sufficient to obtain at least 15 residues of N-tenninal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or silver staia Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibod ’s natural environment will not be present. Ordinarily, however, an isolated polypeptide or antibody is prepared by at least one purification step.The term “monoclonal antibody” as used herein 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 and / or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. In some embodiments, monoclonal antibodies have a C-tenninal cleavage at the heavy chain and / or light chain. For example, 1, 2, 3, 4, or 5 amino acid residues are cleaved at the C-terminus of heavy chain and / or light chain. In some embodiments, the C-terminal cleavage removes a C-terminal lysine from the heavy chain in some embodiments, monoclonal antibodies have anN-terroinal cleavage at the heavy chain and / or light chain For example, 1, 2, 3, 4, or 5 amino acid residues are cleaved at the N-terminus of heavy drain and / or light chain. In some embodiments truncated forms of monoclonal antibodies can be made by recombinant techniques. In some embodiments, monoclonal antibodies are highly specific, being directed against a single antigenic site in some embodiments, monoclonal antibodies are highly specific, being directed against multiple antigenic sites (such as a bispecific antibody or a multispecific antibody). 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. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety' of techniques, including, for example, the hybridoma method, recombinant DNA methods, phage-display technologies, and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.The terms “full-length antibody,” “intact antibody” or “whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment. Specifically , wholeantibodies include those with heavy and light chains including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some eases, the intact antibody may have one or more effector functions.An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding region and / or the variable region of the intact antibody, and or the constant region of the intact antibody. Examples of an antibody fragment include the Fc region of the antibody, a portion of the Fc region, or a portion of tire antibody comprising the Fc region. Examples of antigen-binding antibody fragments include domain antibodies (dAbs), Fab, Fab’, F(ab')2 and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et ah, Protein Eng 8(10): 1057-1062

[1995] ); single-drain antibody molecules, and muliispecific antibodies formed from antibody fragments Single heavy chain antibodies or single light chain antibodies can be engineered, or in the case of the heavy chain, can be isolated from camelids, shark, libraries or mice engineered to produce single heavy chain molecules.Papain digestion of antibodies produced two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CHI) Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab’)2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity' and is still capable of cross-linking antigen. Fab’ fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. The Fc fragment comprises the catfeoxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences and glycan in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.“Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary', to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed toachieve maximal alignment over Hie full length of the sequences being compared. For example, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A Hat has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:100 times the fraction XJY where X is the number of amino acid residues scored as identical matches by the sequence in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity' of A to B will not equal the % amino add sequence identity of B to A.Antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibod -dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptors); and B cell activation.“Binding affinity” as used herein refers to the strength of the non-covalent interactions between a single binding site of a molecule (e.g., a cytokine) and its binding partner (e.g., a cytokine receptor). In some embodiments, the affinity of a binding protein (e.g., a cytokine) can generally be represented by a dissociation constant (Kd). Affinity canbe measured by common methods known in the art, including those described herein.An “isolated” nucleic acid molecule encoding the cytokine polypeptides described herein is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it was produced. In some embodiments, the isolated nucleic acid is free of association with all components associated with the production environment. The isolated nucleic acid molecules encoding tire polypeptides and cytokine polypeptides herein is in a form other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from nucleic acid encoding the polypeptides and c tokine polypeptides herein existing naturally in ceils.The term “pharmaceutical formulation" refers to a preparation that is in such form as to permit the biological activity of the active ingredient to be effective, and that contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered.Such formulations are sterile“Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that arenontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and oilier organic acids; antioxidants including ascorbic acid: low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.As used herein, the terns ‘'treatment” refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. An individual is successfully “treated”, for example, if one or more symptoms associated with a disorder (e. g., a neoplastic disease ) are mitigated or eliminated. For example, i individual is successfully “treated” if treatment results in increasing the quality of life of those suffering from a disease, decreasing the dose of other medications required for treating the disease, reducing the frequency of recurrence of the disease, lessening severity of the disease, delaying the development or progression of the disease, and / or prolonging survival of individuals.As used herein, “in conjunction with” or “in combination with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” or “in combination with" refers to administration of one treatment modality before, during or after administration of the other treatment modality to the individualAs used herein, the tern) “prevention” includes providing prophylaxis with respect to occurrence or recurrence of a disease in an individual. An individual may be predisposed to, susceptible to a disorder, or at risk of developing a disorder, but has not yet been diagnosed with the disorder. In some embodiments, masked cytokines described herein are used to delay development of a disorder.As used herein, an individual “at risk” of developing a disorder may or may not have detectable disease or symptoms of disease, and may or may not have displayed detectable disease or symptoms of disease prior to the treatment methods described herein. “At risk” denotes that an individual lias one or more risk factors, which are measurable parameters that correlate with development of the disease, as known in the art. An individual having one or more of these risk factors has a higher probability of developing the disorder than an individual without one or sno re of these risk factors.An “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary.to achieve the desired or indicated effect, including a therapeutic or prophylactic result.An effective amount can be provided in one or more administrations. A “therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement of a particular disorder. A therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the masked cytokine are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at the dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at the earlier stage of disease, the prophylactically effective amount can be less than the therapeutically effective amount“Chronic” administration refers to administration of tire medicaments) in a continuous as opposed to acute mode, so as to main the initial therapeutic effect (activity) for an extended period of time. “Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cy clic in nature.As used herein, an “individual” or a “subject” is a mammal. A “mammal” for purposes of treatment includes humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. in some embodiments, the individual or subject is human.9. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Tt is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested So perso ns skilled in the art: and are to be included within the spirit and purview of this application and scope of the appended claims. Although some examples describe the engineering, production, and / or testing of “masked” versions of an IL-2 polypeptide construct, some examples also employ parental “non-masked” versions of the IL-2 polypeptide construct, such as for comparison, or other constructs that include one or more of the components described herein that are tested as controls for comparison. Accordingly, the description of, for ins tance, testing done on masked IL-2 polypeptide constructs does not necessarily mean that non- masked versions of the construct were not also tested.Example 1: Engineering of Masked IL-2 PolypeptidesMasked IL-2 polypeptide are generated in accordance with the teachings herein. In the subsequent examples, some experiments involve use of the masked IL-2 polypeptide constructs in monomer form, and some experiments involve use of tire masked IL-2 constructs in dimer form, such as a dimer formed through disulfide bonds linking two copies of the same masked polypeptide construct (homodimer), or a heterodimer formed by two different polypeptides (see, e.g.. Table 5).Masked IL-2 polypeptide constructs are generated that include an IL-2 polypeptide or functional fragment thereof, a masking moiety, and a half-life extension domain, such as i antibody or fragment thereof (e.g., an Fc region, heavy chain, and / or light chain). Some IL-2 polypeptide constructs are also generated that include an IL-2 polypeptide or functional fragment thereof linked to a half-life extension domain without also including a masking moiety'. Some of the constructs also include a linker that comprises a cleavabie peptide and links the masking moiety to the TL-2 polypeptide or functional fragment thereof, thereby resulting in an activatable masked IL-2 polypeptide construct. Some of the constructs also include a linker that links the IL-2 polypeptide or functional fragment thereof to the half- life extension domain. Some of tire constructs also include a linker that links the IL-2 polypeptide or functional fragment thereof to the masking moiety. The masked IL-2 polypeptide constructs that do not include a cleavabie peptide in the linker that links the IL-2 polypeptide or functional fragment thereof to the masking moiety are also referred to as non-activaiable masked IL-2 polypeptide constructs or non- activatable IL-2 polypeptide constructs because they do not include a cleavabie peptide. The structure and composition of exemplary IL-2 polypeptide constructs are provided in Table 3.Table 3:Also generated are masked IL-2 polypeptide constructs that include an IL-2 polypeptide or functional fragment thereof, a first masking moiety, a second masking moiety, and a half-life extension domain, such as albumin, an antibody or fragment thereof (e.g., an Fc region, heavy chain, and / or light chain), an albumin-binding peptide, an IgG-bindmg peptide, or a polyamino acid sequence. Some of the constructs also include a linker that links the first masking moiety to the IL-2 polypeptide or functional fragmentthereof. Some of the constructs also include a linker that links the second masking moiety to the IL-2 polypeptide or functional fragment thereof. Some of the constructs include a cleavable peptide in the linker linking the first masking moiety to the IL-2 polypeptide or functional fragment thereof and / or the linker linking the second masking moiety to the IL-2 polypeptide or functional fragment thereof, thereby resulting in an activatable masked IL-2 polypeptide construct. Some of the constructs also include a linker linking the second masking moiety to the half-life extension domain. The masked IL-2 polypeptide constructs that do not include a cleavable peptide in either of the linkers that link the IL-2 polypeptide or functional fragment thereof to the first masking moiety or the second masking moiety are also referred to as non-activatable masked IL-2 polypeptide constructs or non-activatable IL-2 polypeptide constructs because they do not include a cleavable peptide. The structure and composition of exemplary IL-2 polypeptide constructs are provided in Table 4Table 4:Also generated are masked IL-2 polypeptide constructs that include an IL-2 polypeptide or functional fragment thereof, a masking moiety, a first half-life extension domain, and a second half-life extension domain, an antibody or fragment thereof (e.g., an Fc region, heavy chain, and or light chain). The masking moiety is linked to the first half-life extension domain, the IL-2 polypeptide or functional fragment thereof is linked to the second half-life extension domain, and the first half-life extension domain and the second half-life extension domain contain modifications promoting the association of the first and the second half-life extension domain. In one exemplary embodiment, the masking moiety is linked to the first half-life extension domain, and the IL-2 polypeptide or functional fragment thereof is linked to the second half-life extension domain, and the first half-life extension domain and the second half-life extension domain contain modifications promoting the association of the first and the second half-life extension domain in one exemplary7embodiment of a non-masked IL-2 polypeptide construct, the embodiment comprises an IL-2 polypeptide or functional fragment thereof linked to a first half-life extension domain, and comprises a second half-life extension domain, where the IL-2 polypeptide or functional fragment thereof is linked to the first half-life extension domain, and the second half-life extension domain. Some of the constructs also include a linker that links the masking moiety to the first half-life extension domain, and / or a linker that links the IL-2 polypeptide or functional fragment thereof to the second half-life extension domain. The first and second half-life extension domain of some of the constructs are also linked. In some constructs, the first and second half-life extension domain of some ofthe constructs are linked by a linker. Some of the constructs include a cleavabie peptide in the linker linking the masking moiety to the first half-life extension domain and / or the linker linking the IL.-2 polypeptide or functional fragment thereof to the second half-life extension domain, thereby resulting in an activatable masked IL-2 poly peptide construct. The masked IL-2 polypeptide constructs that do not include a cleavabie peptide in either the linker that links the IL-2 polypeptide or functional fragment thereof to the second half-life extension domain or the linker that links the masking moiety to the first half-life extension domain are also referred to as non-activatable masked IL-2 polypeptide constructs or non-activatable IL-2 polypeptide constructs because they do not include a cleavabie peptide. The structure and composition of exemplary IL-2 polypeptide constructs are provided in Table 5.£ re t—Example ?; In vitro char ctenigajiioa of masked IL-2The masked EL-2 polypeptide constructs generated in Example 1 are characterized rising several cellular and functional assays in vitro.Production Plasmids encoding the constructs (e.g., masked IL-2 polypeptide constructs) were transfected into either Expi293 cells (Life Technologies A14527) or HEK293-6E cells (National Research Council; NRC). Transfections were performed using 1 mg of tola! DNA using PEIpro (Polyplus Transfection, 115-100) in a 1 : 1 ratio with the total DMA. The DNA and PEI were each added to 50 mL of GptiMem (Life Technologies 31985088) medium and sterile filtered. The DNA and PEI were combined for 10 minutes and added to the Expi293 ceils with a cell density of 1.8 - 2.8 x 10®cells / tnL or 0.85-1.20 x 10®cells / m, for expi293 cells or HEK293 cells, respectively, and a viability of at least 95% The HEK293-6E transfection was performed with a cell density of and a viability of at least 95%, following the same protocol used for the Expi293 transfections. After 5-7 days, the cells were pelleted by centrifugation at 3000 x g and the supernatant was filtered through a 0.2 mhi membrane Protein A resin (CaptivA, Repligen CA-PRI-0005) was added to the filtered supernatant and incubated for at least 2 hours at 4 °C with shaking. The resin was packed into a column, washed with 15 column volumes of 20 mM citrate, pH 6.5, and then washed with 15 column volumes of 20 mM citrate, 500 mM sodium chloride, pH 6 5. The bound protein was eluied from the column with 20 rnM citrate, 100 mM NaCi, pH 2.9.The titer (rag / L) of exemplary constructs produced, including parental (e.g., iron-masked) and masked constructs, is provided in Table 6, below'.Table 6SDS-PA GE AnalysisFor SDS-PA GE analysis, protein samples were made with 4x Laemmli sample buffer (BioRad Catalog Number 1610747). For the reduced samples, 0.1 M Bond Breaker T'CEP Solution (Thermo Scientific 77720) was added and the samples were heated for 5 minutes at 65 °C. The proteins were loaded into a12-well NuPage 4- 12 % Bis-Tris Protein Gel (Invitrogen NP0322BOX), with 4 mg of protein loaded per well. The gel was stained using SimplyBlue SafeStain (Invitrogen LC6065).As depicted in FIG. 4, SDS-PAGE analysis was performed on the flow-through (FT) samples (i.e., proteins that did not bind to the Protein A column) and the eluted (E) samples (i.e., proteins that bound to the Protein A column and were eluted from it) following production and purification of exemplary constructs (AK304, AK305, AK307, AK308, AK309, AK310, AK311, AK312, AK313, AK314, and AK315). This exemplary data demonstrates that constructs as described herein can be successfully produced and purified.Reporter Bioassays Reporter bioassays are performed on masked 1L-2 polypeptide constructs, along with non-masked parental constructs or other controls, to monitor activation of a downstream pathway, such as the JAK- 8TAT pathway.In some studies, HEK-Blue IL-2 reporter cells (Invivogen) were used to test activation of the JAK-STAT pathway in accordance with the following method. HEK-Blue IL-2 cells passage 6 (p6) (97% live) were washed 2x with assay medium (DMEM + 10% heat-inactivated FBS), plated in 3 plated at 5e4 cells / well in 150 uL of assay medium, and rested in assay medium for about 2 hours to allow’ adherence to plate. Each construct tested was diluted to 300 pM in assay medium, then diluted 1:2 down the plate. 50 uL ofeach dilution was added, for a final starting concentration of 75 pM. HEK-Blue IL-2 cell supernatant was harvested after 24 hours, an incubated with Quantibliie (180 uL + 20 uL supernatant), plus 3 wells / plate of assay medium, at 37 deg C for 1 hour. The absorbance was read using a Biotek Neo2 at 625 rim. in some studies, CTLL2 cells were used to test activation of the JAK-STAT pathway in accordance with the following method. CTLL2 cells were plated at 40,000 cell per well in RPM1 with 10% FBS. Dilutions of tiie constructs of interest were added and incubated at 37 degrees. After 6 hours, die Bio-Glo reagent was added and luminescence measured with a BioTek Synergy Neo2 plate reader.Receptor BindingThe binding of the masked IL-2 polypeptide constructs generated in Example 1 is assessed. For tire masked IL-2 polypeptide constructs, in some experiments, ELISA plates are coated with a receptor subunit, such as lL-2Ra (also referred to as CD25), IL- 2Rp (also referred to as CD 122), or lL-2Ry (also referred to as CD 132), or combinations thereof. Dilutions of masked IL-2 polypeptide constructs are allowed to bind to the receptor subunit(s) and are detected using an anti-huFc-HRP detection antibody. Tire binding of the masked IL-2 polypeptide constructs is determined in conditions with and without protease cleavage.On-Cell Receptor BindingThe on-cell receptor binding of the masked IL-2 polypeptide constructs generated in Example 1 is assessed. Dilutions of masked IL-2 polypeptide constructs are allowed to bind to peripheral blood lymphocytes or tissue culture ceils, such as CTL.L2 cells and are detected by fluorescence activated cell sorting (FACS) using an anti-huFc-FITC or anti-aibumm-FITC detection antibody. The binding of the masked IL-2 polypeptide constructs is determined in conditions with and without protease cleavage.Receptor Binding AffinityFor SPR studies testing binding of masked and non-masked IL-2 polypeptide constructs, Reichert Carboxymethyl Dextran Hydrogel Surface Sensor Chips were coated and immobilized with the construct of interest (e.g., a masked IL-2 polypeptide construct or non-masked IL-2 polypeptide construct) at 30ug / mi in IQniM Sodium Acetate, pH 5.0 via amine coupling with EDC and JMHS. Dilutions of CD25- Fe or Fc-CD122 inPBST (CD25: 16 nM, 8 nM, 4 nM, 2 nM, 1 nM and CD122: 500 nM, 250 nM, 125 nM, 62.5 nM, 31.25 nM) were prepared. Using a Reichert 4Channel SPR, dilutions of CD25 or CD ! 22 were flowed over the clips with the immobilized construct to determine the on rate at 25 degrees C At equilibrium (approximately 3 minutes), the flow buffer was changed to PBST, to determine the off rates over 6 minutes. Between each ran the chip was regenerated with 10 rnM glycine, pH 2.0.FIGs. 5A-5D depicts the efficacy of mutations on EL-2 which prevent binding to its alpha-receptor, using SPR analy sis that tested the binding of an exemplary masked IL-2 polypeptide construct (AK168) toCD25-Fc. FIG. 5A depicts the interaction between AK168 and CD25-Fc, FIG. SB depicts the interaction between AK168 activated with MMP and CD25-Fc, and FIG. 5C depicts the interaction between a recombinant human IL-2 (rliIL-2) control and CD25-Fc. FIG. 5D provides a table summarizing the data obtained for the association constant (ka), dissociation constant (kd), equilibrium dissociation constant (KD), as well as the CM2 value and U-value for each interaction. These results demonstrate that this exemplary' masked IL-2 polypeptide construct (AK168) did not demonstrate detectable binding to CD25- Fc, while the wild-type rhIL-2 control did demonstrate detectable binding.FIGs. 6A-6D depicts the inasking of IL-2 towards its beta-receptor as well as restoration of binding post activation with protease, using SPR analysis that tested the binding of an exemplary masked IL-2 polypeptide constant (AK111) to CD122-Fc. FIG. 6A depicts the interaction between AK111 and CD 122-Fc, FIG. 6B depicts the interaction between AK111 activated with MMP and CD 122-Fc, and FIG. 6C depicts the interaction between a recombinant human IL-2 (rhTL-2) control and CD 122-Fc. FIG. 6D provides a table summarizing the data obtained for the association constant (ka), dissociation constant (kd), equilibrium dissociation constant (KD), as well as the CM2 value and U-value for each interaction. These results demonstrate that this exemplary masked IT., -2 polypeptide construct (AK11 G) did not demonstrate detectable binding to CD 122-Fc unless it lias been activated with protease, while the rhIL-2 control did demonstrate detectable binding. Additional exemplary' SPR data is provided below in Table 7 for various constructs tested, including masked and non-masked constructs. For some structures, when applicable, the KD was determined for the construct with or without having been previously cleaved by a protease.Table 7AK035 No binding detected 110 nMCleavageThe cleavage rate of the masked IL-2 polypeptide constructs is assessed by conducting receptor- binding assays, as described above, after incubation of the masked IL-2 peptide constructs in the presence or absence of a protease, and with the protease, if any, inactivated at various time points, such as by the addition of EDTA. The cleavage rate is also assessed using reducing and non-reducing polyacrylamide gel electrophoresis (PAGE) and by mass spectrometry whole mass and peptide map analyses. The cleavage rate is also assessed using an ex vivo assay in which the masked IL-2 polypeptide constructs are exposed to human, mouse, or eynomoigus monkey peripheral blood lymphocytes, or normal human tissue or human tumor tissue.For some protease activation studies, MMP10 was diluted to ."50 ng / uL in MMP cleavage buffer and activated with IroM APMA for 2 h at 37 °C. 5 pL of protease (250 ng total) of the activated protease was incubated with luM of masked cytokine constructs (e.g., masked IL-2 polypeptide constructs) and incubated at 37 degrees for 2 hours. Cleavage was assessed by SDS-PAGE using AnykD™ Criterion™ TGX Stain-Free™ Protein Gels. A similar approach is taken to test cleavage by other proteases.FIG. 7A depicts an exemplary structure of a masked IL-2 polypeptide prior to (left) and alter (right) cleavage by a protease, such as a protease associated with the tumor environment FIG. 7B depicts SDS- PAGE analysis of an exemplary masked IL-2 polypeptide construct that was incubated in the absence (left lane) or presence (right lane) of the MMP10 protease.ProliferationProliferation of IL-2 responsive tissue culture ceil lines, such as CTLL2, YT, TF1B, LGL, HH, and CT6, following treatment with the masked IL-2 polypeptide constructs generated in Example 1 is assessed. For experiments involving the masked IL-2 polypeptide constructs, cells are plated in 96 well tissue culture plates in media lacking IL-2 for 2-4 hours and then treated with the masked IL-2 poly peptide constructs at various concentrations. After incubation at 37 degrees for 24-48 horns, the cell number is determined by the addition of MTS, aiamar blue, iuciferase, or a similar metabolic detection reagent, and the colorimetric, fluorescent or iuciferase readout detected by a plate spectrophotometer reader.The proliferation of immune cells following treatment with the masked IL-2 polypeptide constructs generated in Example 1 is also assessed. Human, mouse, or eynomoigus peripheral blood mononuclear cells (PBMCs) are treated with the constructs at various concentrations, and the proliferation of cell types, such as Natural Killer (NK) cells, CD8+ T cells, CD4+ T cells, and / or Treg cells, is determined by staining for the particular ceil type and analysis via fluorescence activated ceil sorting (FACS). In some experiments, some PBMCs are treated with controls for comparison. In some experiments, some PBMCsare treated with aldesleukin as a control for the masked IL-2 polypeptide treatment in some experiments, the masked IL-2 polypeptide constructs are tested in conditions with and without protease cleavage (e.g., activation) in some experiments, the NK eelis are stained as CD45+ CD3- CD56+, the CDS-;- T cells are stained as CD45+ CD3+ CD8+, the CD4+ T cells are stained as CD45+ CD3+ CD4+ CD25-, and the Treg cells are stained as CD45+ CD3+ CD4+ CD25+ FOXP3+. In some experiments, the PBMCs are treated for a period of five days. In sortie experiments, the PBMCs are also stained with Ki67, a marker of cell proliferation. In some experiments, the PBMCs are labeled with CF8E (Signia-Aldrich) prior to treatment and proliferation is measured by determining the extent of CFSE dilution. In some experiments, each construct, as well as aldesleukin and / or other controls, is administered at one or more concentrations, such as one or more concentrations ranging from 0 0001 nM to 500 uM.STATS ActivationThe activation of Signal Transducer and Activator of Transcription 5 (STAT5) following treatment with the masked IL-2 polypeptide constructs generated in Example 1 is also assessed. PBMCs are treated with the constructs for a specified period of time and are then immediately fixed to preserve the phosphorylation status of proteins, such as STATS in some experiments, some PBMCs are treated with controls for comparison. In some experiments, some PBMCs are treated with aldesleukin as a control for the masked IL-2 polypeptide treatment. In some experiments, the masked IL-2 polypeptide constructs are tested in conditions with and without protease cleavage (e.g., activation). In some experiments, the PBMCs are treated for 10 minutes, 15 minutes, 20 minutes, or 25 minutes. In some experiments, each construct, as well as aldesleukin and / or other controls, is administered at one or more concentrations, such as one or more concentrations ranging from 0.0001 nM to 500 nM. In some experiments, the fixed and permeabilized PBMCs are then stained with an antibody specific for phosphoiylated STAT5 (phospho- 8TAT5) and are analyzed by flow cytometry. In some experiments, total and phosphoiylated levels of STAT5 are measured. The phospho- STATS status of certain cell types, such as NK cells, CD8+ T cells, CD4-T- T cells, and / or Treg cells, is determined b stainin for the particular cell type. In some experiments, the NK cells are stained as CD45+ CD3- CD56+, the CD8+ T cells are stained as CD45+ CD3+ CD8+, tiie CD4+ T cells are stained as CD45+ CD3+ CD4+ CD25-, and the Treg cells are stained as CD45+ CD 3+ CD4+ CD25+ FOXP3+.The activation of STATS in the mouse cell lines, such as CTLL-2 cells, following treatment with the masked IL-2 polypeptide constructs generated in Example 1 is also assessed in some experiments, some CTLL-2 cells are treated with controls for comparison. In some experiments, some CTLL-2 cells are treated with aldesleukin as a control for the masked IL-2 polypeptide treatment In some experiments, the masked IL-2 polypeptide constructs are tested in conditions with and without protease cleavage (e.g., activation). In some experiments, the CTLL-2 cells are treated for 10 minutes, 15 minutes, 20 minutes, or 25 minutes, and are then fixed to preserve the phosphorylation status of proteins, such as STAT5. in some experiments, each construct, as well as aldesleukin and / or other controls, is administered at one ormore concentrations. In some experiments, total and phosphotylated levels of STATS are measured in some studies, the levels of intracellular STATS activation (pSTATS signal) induced by IL-2 was determined by the following method. Frozen human PBMCs were thawed in water bath and added to 39 mL pie-warmed media (RPMI164Q medium plus 10%FBS, 1%P / S, 1% NEA), spun and reconstitute in media at 10E6 celis / rnL. Cells were plated at 5E5 per well cells in a 96 well plate. IL-2 (e.g.. rhIL-2 or an exemplary' IL-2 -containing polypeptide construct) diluted in medium was added to each well, and incubated at 37 °C for 20 min. Cells were then fix with 200ul / well Fixation buffer (eBiosciences) at 4 °C, overnight. After centrifugation, the fixed cells were resuspended in 200ul cold BD Phosf!ow buffer and incubated at 4°C for 30 min. After washing the cells twice, they were treated with Biolegend Human TraStain FcX (2.5 uL in 50 uL total per sample in Staining buffer) for 5 min on ice. Staining antibodies were added; Sul pSTATS- APC (pY694, BD), lOul CD56-BV421 (5.1H11, Biolegend), lOul CD4- PerCP / Cj'5.5 (A 161A1, Biolegend), and lOul CD3-FITC (UCHTl, Biolegend) and incubated for 30 min. on ice, protected from light. Ceils were washed 2 times and resuspended, and analyzed by flow cytometr .FIGs. 8A-8D depict the results from STATS activation studies, as described above, using the exemplary constructs AK032, AK035, AK041, or rhIL-2 as a control. The levels of STAT5 activation (%) are shown for NK cells, CD8+ T cells, effector T cells (Tefi), and regulator T cells (Treg). The AK032 and AK035 constructs include an IL-2 polypeptide linked to an Fc domain, and the AK041 construct includes an IL-2 polypeptide linked to a CD25 domain and a CD 122 domain. As shown, engineered IL-2 polypeptide constructs can, in some embodiments, reduce activation of Treg cells while retaining or enhancing activation of CD8+ T cells and NK cells.FIGs. 9A-9C depict the results from STATS activation studies, as described above, using the exemplary constructs AK081 and AK032. The AK081 construct with and without prior exposure to MMP10 was tested. An isotype control as well as a no IL-2 negative control was also tested. The levels of STAT5 activation (%) are show n forNK cells, CD8+ T cel...

Claims

CLAIMS What is claimed is:

1. A masked IL-12 cytokine comprises a protein heterodimer comprising: a first polypeptide chain comprising:N’ HL1-L1-MM C’ and a second polypeptide chain comprising:N’ HL2-L2-C C’ where HL1 is a first half life extension domain, LI is a first linker, MM is a masking moiety, HL2 is a second half life extension domain, L2 is a second linker, and C is an IL-12 cytokine or functional fragment thereof, wherein the first half-life extension domain is associated with the second half-life extension domain, and wherein one of the first linker or the second linker comprises a proteolytically cleavabie peptide.

2. The masked cytokine of claim 1, wherein the IL-12 polypeptide or functional fragment thereof comprises an IL-12p40 polypeptide or functional fragment thereof covalently linked to an 1L-I2p35 polypeptide or functional fragment thereof.

3. The masked cytokine of claim 2, wherein the IL-12p40 - IL~!2p35 linker is between 5 and 20 amino acids in length.

4. The masked cytokine of claim 2 or 3, wherein the II.- 12p40 -- IL-I2p35 linker is rich in amino acid residues G and S5. The masked cytokine of any one of claims 2-4, wherein the IL-12p40 - IL-12p35 linker comprises SEQ ID NO:

3. (GGGGSGGGGSGGGGS)6. The masked cytokine of any one of claims 2-5, wherein the IL-12p40 polypeptide comprises SEQ ID NO: 1 or an amino acid sequence having at least one amino acid modification as compared to the amino acid sequence of SEQ ID NO: 1.

7. The masked cytokine of claim 6, wherein IL-12p40 polypeptide comprises SEQ TD NO: 1.

8. The masked cytokine of claim 6, wherein IL-12p40 polypeptide comprises at least one amino acid modification to the GAG-binding domain (KSKREKKDRV) as compared to die amino acid sequence of SEQ ID NO: 1.

9. The masked cytokine of claim 8, wherein IL-32p40 polypeptide comprises SEQ ID NO: 57.

10. The masked cytokine of claim 8, wherein IL-12p40 polypeptide comprises SEQ ID NO: 58.

11. The masked cytokine of any one of claims 6-10, wherein IL-12p40 polypeptide compri es an amino acid sequence having one or snore cysteine substitution mutations as compared to the amino acid sequence of SEQ ID NO: 1.

12. The masked cytokine of claim 11, wherein the 1L-I2p40 polypeptide comprises SEQ ID NO: 59.

33. The masked cytokine of claim 1, wherein the 1L-I2p40 polypeptide comprises SEQ ID NO: 60.

14. The masked cytokine of any one of claims 2-13, wherein the 1L-I2p35 polypeptide comprises SEQ TD NO: 2 or an amino acid sequence having at least one amino acid modification as compared to the amino acid sequence of SEQ ID NO: 2.

15. The masked cytokine of claim 14, wherein the 1L-I2p35 polypeptide comprises SEQ ID NO: 2.

16. Tire masked cytokine of any one of claims 1 to 7, wherein the TL-12 cytokine or functional fragment thereof comprises SEQ TD NO:

417. The masked cytokine of any one of claims 1 to 10, wherein the EL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 61.18 The masked cytokine of any one of claims 1 to 10, wherein the 1L-12 cytokine or functional fragment thereof comprises SEQ ID NO: 62.

19. The masked cytokine of any one of claims 1 to 12, wherein the EL-12 cytokine or functional fragment thereof comprises SEQ ID NO: 63.

20. The masked cytokine of any one of claims 1 to 13, wherein tire H.-12 cytokine or functional fragment thereof comprises SEQ ID NO: 64.

21. The masked cytokine of any one of the preceding claims, wherein the masking moiety comprises an IL-12 cytokine receptor, or a subunit or functional fragment thereof.

22. The masked cytokine of any one of the preceding claims, wherein the masking moiety comprises the extracellular domain of human IL-12Rpl or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12.

23. The masked cytokine of claim 22, wherein the masking moiety comprises residues 24 to 237 of human li., -12Rpl , namely a sequence having SEQ ID NO: 5.

24. The masked cytokine of claim 22, wherein the masking moiety comprises residues 24 to 545 of human IL-12RpL namely a sequence having SEQ ID NO: 6.

25. The masked cytokine of any one of claims 1-21, wherein the masking moiety comprises the extracellular domain of human IL~12Rp2 or a fragment, portion, or variant thereof that retains or otherwise demonstrates an affinity to IL-12.26 The masked cytokine of claim 25, wherein the masking moiety' comprises residues 24 to 212 of human IL-l2Rp2, namely a sequence having SEQ ID NO: 7.

27. The masked cytokine of claim 25, wherein the masking moiety comprises residues 24 to 222 of human IL-12RP2, namely a sequence having SEQ ID NO: 8 or wherein the masking moiety comprises residues 24 to 227 of human IL-12RP2, namely a sequence having SEQ ID NO: 3 1.

28. The masked cytokine of claim 25, wherein the masking moiety comprises residues 24 to 319 of human IE-ί2Kb2, namely a sequence having SEQ ID NO: 9.

29. The masked cytokine of claim 28, wherein the masking moiety comprises at least one amino acid modification as compared to the sequence of SEQ ID NO: 9, optionally wherein said modifications are cysteine substitution mutations.

30. The masked cytokine of claim 29, wherein the masking moiety comprises SEQ ID NO: 6531. The masked cytokine of claim 25, wherein the masking moiety comprises residues 24 to 622 of human IL-12R[32, namely a sequence having SEQ ID NO: 10.

32. The masked cytokine of any one of the preceding claims, wherein the cleavable peptide is from 6 to 10 amino aci s in le gth.33 The masked cytokine of any one of the preceding claims, wherein she cieavable peptide comprises an amino acid sequence of SEQ ID NO: 15.

34. The masked cytokine of any one of the preceding claims, wherein the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 41.

35. The masked cytokine of any one of the preceding claims, wherein the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 42.

36. The masked cytokine of any one of the preceding claims, wherein the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 43.

37. The masked cytokine of any one of the preceding claims, wherein the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 44.

38. The masked cytokine of any one of the preceding claims, wherein the cieavable peptide comprises an amino acid sequence of SEQ ID NO: 45.

39. The masked cytokine of any one of the preceding claims, wherein the first polypeptide chain comprises:N’ HLl-non-deavable Ll-MM C’ and the second poly peptide chain comprisesN’ HL2-deavable L2-C C’40. The masked cytokine of claim 39, wherein the non-cleavable linker is between 3 and 18 amino acids in length.41 The masked cytokine of claim 39, wherein she non-cleavable linker is between 3 and 15 amino acids in length.

42. The masked cytokine of any one of claims 30 to 41, wherein the non-cleavable linker is rich in amino acid residues G and S.

43. The masked cytokine of any one of claims 39 to 42, wherein the non-cleavable linker includes [(G)nS], where n=4 or 5.

44. The masked cytokine of any one of claims 39 to 43, wherein the non-cleavabie linker comprises art amino acid sequence as shown in SEQ ID NO: 12 (GGGGS).

45. The masked cytokine of any one of claims 39 to 43, -wherein the non-cleavabie linker comprises an amino acid sequence as shown in SEQ ID NO: 13 (GGGGSGGGGS).

46. The masked cytokine of any one of claims 39 to 43, wherein the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 14 (GGSGGGSGGGGGS).

47. The masked cytokine of any one of claims 39 to 42, wherein the non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 54 (GGSGGSGGSGGSGGSSGP).

48. The masked cytokine of any one of claims 39 to 42, wherein lire non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 55 (PGGSGP).

49. The masked cy tokine of any one of claims 39 to 42, wherein tire non-cleavable linker comprises an amino acid sequence as shown in SEQ ID NO: 56 (GGSPG).

50. The masked cytokine of any one of claims 39 to 49, wherein the cleavable linker comprises a proteolytieally cleavable peptide (CP) flanked on both sides by a spacer domain (SD):SD1-CP-SD2 where SD 1 and SD2 are different, such that the first polypeptide chain comprises:N’ HLl-noii-cIeavable Ll-MM C” and the second polypeptide chain comprises:N’ HL2- 8D1-CP-SD2 -C C51. The masked cytokine of claim 50, wherein the first spacer domain (SD 1) is between 3 and 10 a ino acids in length.

52. The masked cytokine of claims 50 or 51, wherein SD1 comprises SEQ ID NO:

16. (GGSGGS)53. The masked cytokine of claims 50 or 51 , wherein SD1 comprises SEQ ID NO:

37. (GGSGGSGGS)54. The masked cytokine of any one of claims 50 to 53, wherein the second spacer domain (SD2) is between 3 and 6 amino acids in length.

55. The masked cytokine of any one of claims 50 to 54, wherein SD2 comprises SEQ ID NO: 18.(SGP)56 The masked IL-2 cytokine of claim 50, wherein lire proteolydcaily cleavable linker comprises SDi- CP-SD2 where SD 1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer domain, and wherein CP has an amino acid sequence as shown in SEQ TD NO: 44 and SD2 has an amino acid sequence as shown in SEQ ID NO: 18.

57. The masked IL -2 cytokine of claim 50, wherein the proteolydcaily cleavable linker comprises SD1- CP-SD2 where SD 1 is a first spacer domain, CP is a cleavable peptide and SD2 is a second spacer do ain, nd wherein CP has an amino acid sequence as shown in SEQ ID NO: 45 and SD2 has an amino acid sequence as shown in SEQ ID NO: 18.

58. The masked cytokine of any one of claims 50 to 54, wherein the cieavable linker comprises SEQ ID NO:

19. (GGSGGSVPLSLYSGP)59 The masked cytokine of any one of claims 50 to 54, wherein the cieavable linker comprises SEQ ID NO:

20. (GGSGGSGGSVPLSLYSGP)60 Tire masked cytokine of claim 50, wherein the cieavable Sinker comprises SEQ ID NO:

46. (GGSOGSMPYDLYHPSGP)61. The masked cytokine of claim 50, wherein the cleavable linker comprises SEQ ID NO:

47. (GGSGGSGGSMPYDLYHPSGP)62. The masked cytokine of claim 50, wherein the cleavable linker comprises SEQ ID NO:

48. (GGSGGSDSGGFMLTSGP)63. The masked cytokine of claim 50, wherein the cleavable linker comprises SEQ ID NO: 49 (GGSGGSCGSDSGGFMLTSGP)64. The masked cytokine of claim 50, wherein the cieavable linker comprises SEQ ID NO:

50. (GGSGGSRAAA VKSPSGP)65. The masked cytokine of claim 50, wherein the cieavable linker comprises SEQ ID NO:

51. (GGSGGSGGSRAAAVKSPSGP)66. The masked cytokine of claim 50, wherein the cieavable linker comprises SEQ TD NO:

52. (GGSGGSI S S GLL SGRS SGP)67. The masked cytokine of claim 50, wherein the cleavahle linker comprises SEQ ID NO: 53 (GGSGGSGGSISSGLLSGRSSGP)68. The masked cytokine of any one of the preceding claims, wherein the first half-life extension domain comprises a first IgGl Fc domain or a fragment thereof and the second half-life extension domain comprises a second IgGl Fc domain or a fragment thereof.

69. The masked cytokine of any one of the preceding claims, wherein the first and / or second Fc domains each contain one or more modifications that promote tire non-covalent association of tire first and the second half-life extension domains.

70. The masked cytokine of any one of the preceding claims, wherein the first half-life extension domain comprises SEQ ID NO: 25 (Y349C; T366S; L38A; Y407V; and N297A) and the second half-life extension domain comprises SEQ ID NO 26 (S354C, T366W and N297A).

71. The masked cytokine of any one of the preceding claims, wherein the first half-life extension domain comprises SEQ ID NO: 27 (Y349C; T366S; L38A; Y407V, N297A and 1253 A) and the second half-life extension domain comprises SEQ ID NO: 28 (S354C, T366W, N297A and 1253 A).

72. Tire masked cytokine of claim 1, wherein the first polypeptide chain comprises an amino acid sequence of SEQ ID NO:34 and a second polypeptide chain comprises an amino acid sequence of SEQ ID NO: 40.

73. A cleavage product capable of binding to IL-12R, the cleavage product comprising an IL-12 cytokine or functional fragment thereof, preparable by proteoly tic cleavage of the cleavahle peptide in a masked IL-12 cytokine as defined in any of claims 1-42.

74. A cleavage product of a masked IL-12 cy tokine, where the cleavage product is capable of binding to IL-12R, the cleavage product comprising a polypeptide comprising:PCP-SD2-C wherein PCP is a portion of a proteolytieally cleavahle peptide; SD2 is a spacer domain; and C is an IL-12 cytokine or functional fragment thereof.

75. The cleavage p roduct of claim 74, whe rein PCP is a portion of a proteolytieally cleavahle peptide as defined in any of claims 32 to 38.

76. The cleavage product of claims 74 or 75, wherein SD2 is a spacer domain as defined in any of claims 54 to 55.

77. The cleavage product of any one of claims 74 to 76, wherein C is an IL-12 cytokine or functional fragment thereof as defined in any of claims 2-20.

78. The cleavage product of any one of claims 74 to 77, wherein the cleavage product comprises an amino acid sequence having about or at least about 85%, 86%>, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 29.

79. The cleavage product of claim 78, wherein the cleavage product comprises an amino acid sequence of SEQ ID NO: 29.

80. A nucleic acid encoding the masked IL-12 cytokine of any one of claims 1-72 or encoding one of the polypeptide chains of a masked IL-12 cytokine of any one of claims 1 to 72.81 A vector comprising the nucleic acid of claim 8082. A host cell comprising nucleic acid encoding the masked TL-! 2 cytokine of any one of claims 1 to 72.

83. A composition comprising the masked IL-12 cytokine of any one of claims 1-72.

84. A pharmaceutical composition comprising the masked IL-12 cytokine of any one of claims i- 72 and a pharmaceutically acceptable carrier.

85. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition is in single unit dosage form.

86. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition is formulated for intravenous admini tration and is in single unit dosage form.

87. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition is formulated for injection and is in single unit dosage form.

88. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition is a liquid and is in single unit dosage form.89 A kit comprising the masked IL-12 cytokine of any one of claims 1-41, or the composition of claim 83, or the pharmaceutical composition of claims 84 to 88.

90. A method of producing a masked IL-12 cytokine as defined in any one of claims 1 to 72 comprising culturing the host cell of claim 82 under a condition that produces the masked IL- 12 cytokine.

91. A nucleic acid encoding the cleavage product of any one of claims 73 to 79.

92. A composition comprising the cleavage product of any one of claims 73 to 79.

93. A pharmaceutical composition comprising the cleavage product of any one of claims 73 to 79, and a pharmaceutically acceptable carrier.

94. A masked IL-12 cytokine as defined in any one of claims 1 to 72 for use in medicine.95 A cleavage product as defined in any one of claims 73 to 79 for use in medicine.

96. A method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a masked IL-12 cytokine according to any one of claims 1 to 72.

97. A method of treating or preventing cancer in a subject, the method comprising administering to rite subject an effective amount of a composition according to claims 83 or 92.

98. A method of treating or preventing cancer in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to any one of claims 84 to 88 and 93.

99. A method of treating or preventing cancer in a subject the method comprising administering to the subject an effective amount of a masked IL-12 cytokine as defined in any one of claims 1 to 72, whereby the masked cytokine is proteolytically cleaved in vivo to produce a cleavage product as defined in any one of claims 73 to 79.

100. A method of treating or preventing cancer in a subject, the method comprising a step of producing a cleavage product in vivo that is capable of binding to its cognate receptor, where the cleavage product is as defined in any one of claims 73 to 79.101 A method according to any one of claims 96-100..wherein the cancer is a solid tumor102. A masked IL-12 cytokine as defined in any one of claims 1 to 72 foruse in treating orpreventing cancer.

103. A masked IL-12 cytokine as defined in any one of claims 1 to 72 for use in a method of treating or preventing cancer, the method comprising administering to the subject an effective amount of the masked IL-12 cytokine, whereby the masked cytokine i proieolytically cleaved in vivo to produce a cleavage product as defined in any one of claims 73 to 79.

104. A masked IL-12 cytokine for use according to claim 103, wherein the cancer is a solid tumor.

105. A cleavage product as defined in any one of claims 73 to 79 foruse in treating or reventing cancer.

106. A cleavage product as defined in any one of claims 73 to 79 for use in a method of treating or preventing cancer, the method comprising a step of administering a masked cytokine as defined in any one of claims 1 to 72 to a patient, thereby producing the cleavage product by proteolytic cleavage of the masked cytokine in vivo.

107. A cleavage product as defined in any one of claims 73 to 79 for use in a method of treating or preventing cancer in a subject, the method comprising a step of producing the cleavage product by in vivo proteolytic cleavage from a masked cytokine as defined in any one of claims 1 to 72 that lias been administered to the subject.

108. A cleavage product for use according to any one of claims 105 to 107, wherein the cancer is a solid tumor.

109. A pharmaceutical composition according to any one of claims 84 to 88 and 93, for use in treating or preventing cancer.1 ! 0. A pharmaceutical composition for use according to claim 109, wherein the cancer is a solid tumor.