Recombinant IL-12 Albumin Binding Domain Fusion Protein for Use in Methods of Treating Cancer - Patent application

Abstract

The present disclosure provides methods for treating cancer, such as an advanced solid tumor, in a subject in need thereof by administering to the subject an effective first dose of an IL-12 albumin binding domain (ABD) fusion protein, and every three or four weeks after administration of the first dose, an effective second dose of the IL-12 ABD fusion protein, wherein the second dose is greater than the first dose.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 421,846, filed November 2, 2022, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure generally provides methods for treating cancer using IL-12 albumin binding domain (ABD) fusion proteins. Sequence Listing

[0003] This application contains a Sequence Listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML file has the file name 116076_5020_WO_Sequence_Listing.xml, was created on October 30, 2023, and is 15,000 bytes in size. [Background technology]

[0004] IL-12 can mediate immune effector functions in a manner compatible with enhancing pro-inflammatory endogenous antitumor immune responses (see, e.g., Boggio et al., J Exp Med 188:589-96 (1998); Cavallo et al., Cancer Res 59:414-21 (1999); Yu et al. Int Immunol 8:855-65 (1996); Nastala et al., J Immunol 153:1697:706 (1994); Brunda et al., J Exp Med 178: 1223-30 (1993)). IL-12 induces inflammatory Th1 CD4+ T cell responses and inhibits CD8+ T cell responses. IL-12 is known to enhance T cell cytotoxicity. Studies have also shown that IL-12-mediated secretion of IFNγ by T cells can reverse T cell anergy and confer resistance to immunosuppressive regulatory T cells on effector T cells. IL-12's ability to activate the adaptive and innate immune systems as well as to further modulate an otherwise immune-hostile tumor microenvironment makes it an ideal candidate for tumor immunotherapy.

[0005] Serum albumin has a long half-life ranging from 2 to 4 weeks due to recycling by the neonatal Fc receptor (FcRn). Albumin is taken up by endothelial cells via macropinocytosis and binds to FcRn in a pH-dependent manner in the acidic environment of early endosomes. Albumin-FcRn binding diverts albumin molecules from degradation in the lysosomal compartment and redirects them to the plasma membrane, where they are released back into the plasma due to the neutral pH.

[0006] The albumin-binding domain (ABD) fusion proteins described in U.S. Patent No. 11,028,166 are useful for extending the half-life of biological agents (e.g., interleukins and antibodies). Such ABDs do not compete with FcRN for albumin binding, and bind to albumin in a pH range that allows the ABD to undergo FcRn-driven endosomal albumin recycling when bound to albumin. Thus, ABD-containing biological agents can use the albumin-FcRn pathway to avoid lysosomal degradation, resulting in a longer blood half-life than counterparts lacking the ABD. Furthermore, such ABD-containing therapeutic agents are favorably localized in tumors, which are known to contain high levels of serum albumin. Therefore, such ABD-containing therapeutic agents are particularly useful for the treatment of cancer. Summary of the Invention

[0007] Provided herein are methods for treating cancer using IL-12 albumin binding domain (ABD) fusion proteins.

[0008] In one aspect, the disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject in need thereof an effective first dose of an IL-12 albumin binding domain (ABD) fusion protein, and every three or four weeks after administration of the first dose, administering an effective second dose of the IL-12 ABD fusion protein, wherein the second dose is greater than the first dose.

[0009] In one aspect, the disclosure provides a method of achieving a clinical response or partial clinical response of a solid tumor in a human patient, comprising administering to the human patient an effective first dose of an IL-12 albumin binding domain (ABD) fusion protein, and every two, three, or four weeks after administration of the first dose, administering an effective second dose of the IL-12 ABD fusion protein, wherein the second dose is greater than the first dose.

[0010] In one embodiment, an effective second and subsequent doses of an IL-12 ABD fusion protein are administered every three weeks following administration of the first dose.

[0011] In one embodiment, an effective second and subsequent doses of an IL-12 ABD fusion protein are administered every four weeks following administration of the first dose.

[0012] In one embodiment, the first dose is from about 25 ng / kg to about 750 ng / kg.

[0013] In one embodiment, the first dose is about 150 ng / kg.

[0014] In one embodiment, the second and subsequent doses are from about 50 ng / kg to about 1.5 μg / kg.

[0015] In one embodiment, the second and subsequent doses are about 300 ng / kg.

[0016] In one embodiment, the second and subsequent doses are about 540 ng / kg.

[0017] In one embodiment, the second and subsequent doses are about 750 ng / kg.

[0018] In one embodiment, the first dose, and the second and subsequent doses are administered intravenously.

[0019] In one embodiment, the first dose, and the second and subsequent doses are administered subcutaneously.

[0020] In one embodiment, the albumin binding domain of the IL-12 ABD fusion protein comprises a variable heavy chain domain comprising SEQ ID NO: 2, or a variant thereof, and a variable light chain domain comprising SEQ ID NO: 6, or a variant thereof.

[0021] In one embodiment, the albumin binding domain is an scFv comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof.

[0022] In one embodiment, the IL-12 of the IL-12 fusion protein is a single-chain IL-12 comprising a p35 subunit covalently linked to a p40 subunit.

[0023] In one embodiment, the p40 subunit has the amino acid sequence of SEQ ID NO: 12 or a variant thereof.

[0024] In one embodiment, the p35 subunit has the amino acid sequence of SEQ ID NO: 13 or a variant thereof.

[0025] In one embodiment, the single-chain IL-12 has the amino acid sequence of SEQ ID NO:10.

[0026] In one embodiment, the IL-12 ABD fusion protein has the amino acid sequence of SEQ ID NO:11.

[0027] In one embodiment, the subject is a human patient.

[0028] In one embodiment, the human patient is an adult human patient.

[0029] In one embodiment, the cancer is a solid tumor.

[0030] In one embodiment, the solid tumor is a solid epithelial or mesenchymal tumor.

[0031] In one embodiment, the method further comprises administering a checkpoint inhibitor to a subject in need thereof.

[0032] In one embodiment, the subject in need thereof has previously received standard treatment or is not a candidate for standard treatment.

[0033] In one embodiment, the solid tumor is an advanced solid tumor. [Brief explanation of the drawings]

[0034] [Figure 1] 1 shows an exemplary IL-12 albumin binding domain (ABD) fusion protein that can be administered. The IL-12 shown is a single-chain IL-12 molecule in which the IL-12A (p35) and IL-12B (p40) components are joined using a polypeptide linker. [Figure 2A] 2A-2B show the albumin binding domain component of an IL-12 albumin binding domain fusion protein that may be used in an IL-12 ABD fusion protein administered using the subject methods provided herein. [Figure 2B] 2A-2B show the albumin binding domain component of an IL-12 albumin binding domain fusion protein that may be used in an IL-12 ABD fusion protein administered using the subject methods provided herein. [Figure 3] FIG. 3 is a series of graphs showing cytokine responses in cohorts that received 50 ng / kg, 100 ng / kg, and 150 ng / kg of IL-12 ABD fusion protein (SON-1010), respectively. [Figure 4] FIG. 4 provides baseline and follow-up results from patients in cohorts M1, M2, and M3 of the study presented in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description I. Overview The present disclosure provides methods for treating cancer, such as an advanced solid tumor, in a subject in need thereof by administering to the subject an effective first dose of an IL-12 albumin binding domain (ABD) fusion protein, and then every three or four weeks after administration of the first dose, an effective second dose of the IL-12 ABD fusion protein, wherein the second dose is greater than the first dose.

[0036] II. Definition In order that this application may be more fully understood, certain definitions are set forth below. These definitions are meant to encompass grammatical equivalents.

[0037] The term "a" or "an" refers to one or more of that entity, i.e., it may refer to multiple referents. Thus, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein. In addition, reference to an "element" by the indefinite article "a" or "an" does not exclude the possibility that more than one element is present, unless the context clearly requires that one, and only one, of the element is present.

[0038] It is noted that the claims may be drafted to exclude all optional elements. As such, this statement is intended as a prerequisite for the use of exclusive terminology, such as "solely," "only," or the use of a "negative" limitation in connection with the recitation of claim elements. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features that can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative exemplary methods and materials are described herein.

[0039] Ranges provided herein are understood to be shorthand for all values ​​within that range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all intervening decimal values ​​between the aforementioned integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to subranges, "nested subranges" extending from either endpoint of the range are specifically contemplated. For example, nested subranges of the exemplary range of 1 to 50 could include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0040] Unless specifically stated otherwise or clear from the context, the term "about" as used herein is understood to mean within the normal tolerance range in the art, for example, within two standard deviations of the mean. About can be understood to mean within 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term about.

[0041] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. When a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, to the tenth of the unit of the lower limit, and any other stated or intervening value within that stated range, is encompassed within the invention unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are encompassed within the invention, subject to any specifically excluded limits in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also encompassed within the invention. Certain ranges herein are presented with numerical values ​​preceded by the term "about." As used herein, the term "about" is used to provide a literal basis for the exact number that follows, as well as for numbers that are close to or approximately the number that follows the term. In determining whether a number is near or approximately a specifically recited number, the near or approximately unrecited number may be a number that, in the context presented, is substantially equivalent to the specifically recited number.

[0043] All publications, patents, and patent applications cited herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, each cited publication, patent, or patent application is incorporated by reference herein to disclose and describe the subject matter in connection with which the publication is cited. The citation of any publication is for disclosure prior to the filing date and should not be construed as an admission that the inventions described herein are not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may require independent confirmation.

[0044] III. IL-12 Albumin Binding Domain Fusion Protein In embodiments, the subject methods described herein are useful for producing IL-12 albumin binding domain (ABD) fusion proteins. Such IL-12 ABD fusion proteins are used, for example, in the treatment of cancer. In some embodiments, the IL-12 albumin binding domain fusion protein comprises an albumin binding domain comprising an antibody variable heavy chain domain comprising a vhCDR1 having the amino acid sequence of SEQ ID NO:3, a vhCDR2 having the amino acid sequence of SEQ ID NO:4, and a vhCDR3 having the amino acid sequence of SEQ ID NO:5 (see Figure 1). In some embodiments, the albumin binding domain comprises a variable light chain domain comprising a vlCDR1 having the amino acid sequence of SEQ ID NO:7, a vlCDR2 having the amino acid sequence of SEQ ID NO:8, and a vlCDR3 having the amino acid sequence of SEQ ID NO:9. In embodiments, the albumin binding domain comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:2 and / or a variable light chain having the amino acid sequence of SEQ ID NO:6. In embodiments, the albumin binding domain comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:2 and a variable light chain having the amino acid sequence of SEQ ID NO:6. In embodiments, the albumin binding domain of the IL-12 albumin binding domain fusion protein is an scFv having the amino acid sequence of A10m3 (SEQ ID NO: 1).

[0045] In embodiments, an IL-12 albumin binding domain fusion protein comprises an albumin binding domain that is a variant of the A10m3 albumin binding domain shown in Figure 1. In exemplary embodiments, the albumin binding domain of an IL-12 albumin binding domain fusion protein comprises a set of six CDRs that have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications compared to the six CDRs of A10m3, as shown in Figure 1. In embodiments, the albumin binding domain of an IL-12 albumin binding domain fusion protein comprises six CDRs that are at least 90%, 95%, 97%, 98%, or 99% identical to the six CDRs of A10m3 (see Figure 1). In embodiments, the albumin binding domain comprises a VH domain and / or a VL domain that have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes from the VH domain and / or VL domain of A10m3, as shown in Figure 1. In embodiments, the albumin binding domain comprises a VH domain and / or a VL domain that is at least 90%, 95%, 97%, 98% or 99% identical to the VH and / or VL of A10m3, as shown in Figure 1. In certain embodiments, variants of the A10m3 albumin binding domain are capable of binding human serum albumin as measured by at least one of a Biacore assay, a surface plasmon resonance (SPR) assay, a flow cytometry assay, and / or a BLI (biolayer interferometry, e.g., Octet assay) assay, the latter being of particular use in many embodiments.

[0046] In certain embodiments, the IL-12 is a single-chain IL-12 polypeptide comprising an IL-12 p35 subunit linked to an IL-12 p40 subunit. In embodiments, the IL-12 single-chain polypeptide advantageously retains one or more of the biological activities of wild-type IL-12. In some embodiments, the single-chain IL-12 polypeptides described herein conform to the formula (p40)-(L)-(p35) from N-terminus to C-terminus, where "p40" is the IL-12 p40 subunit, "p35" is the IL-12 p35 subunit, and L is a linker. In other embodiments, the single-chain IL-12 conforms to the formula (p35)-(L)-(p40) from N-terminus to C-terminus. Any suitable linker can be used in the single-chain IL-12 polypeptide. Suitable linkers include, for example, the amino acid sequence (GGGGS) x where x is an integer from 1 to 10. Other suitable linkers include, for example, the amino acid sequence GGGGGGS. Exemplary single-chain IL-12 linkers that can be used with the subject single-chain IL-12 polypeptides are also described in Lieschke et al., Nature Biotechnology 15:35-40 (1997), which is incorporated by reference in its entirety, particularly for its teachings of IL-12 polypeptide linkers.

[0047] In some embodiments, the IL-12 of the IL-12 albumin binding domain fusion protein comprises a human p40 subunit having the amino acid sequence of SEQ ID NO: 12. In some embodiments, the IL-12 comprises a variant human p40 subunit having from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes compared to SEQ ID NO: 12. In embodiments, the IL-12 comprises a variant human p40 that is at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 12.

[0048] In some embodiments, the IL-12 of the IL-12 albumin binding domain fusion protein comprises a human p35 subunit having the amino acid sequence of SEQ ID NO: 13. In some embodiments, the IL-12 comprises a variant human p35 subunit having from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes compared to SEQ ID NO: 13. In embodiments, the IL-12 comprises a variant human p40 that is at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 13. Table 1 [Table 1-1] [Table 1-2] [Table 1-3]

[0049] IV. Methods of Treating Cancer Provided herein are methods for treating a cancer solid tumor (e.g., a solid epithelial tumor or a mesenchymal tumor) in a subject, such as a human patient, in need of such treatment. Such methods may include administering (e.g., subcutaneously or intravenously) to a subject in need thereof an effective first dose (desensitizing dose) of an IL-12 albumin-binding domain (ABD) fusion protein (e.g., IL12-FHAB or SON-1010) disclosed herein, and administering an effective second dose (maintenance dose) of an IL-12 ABD fusion protein disclosed herein every 2 to 6 weeks after administration of the first dose, where the second dose is greater than the first dose. In some embodiments, the first and second doses are clinically effective doses. The subject in need thereof may have previously received standard therapy or may not be a candidate for standard therapy. In some embodiments, the subject in need thereof may additionally be administered an immune checkpoint inhibitor, either simultaneously with or separately from the first and / or second doses. In some embodiments, the IL-12 albumin binding domain (ABD) fusion protein is administered subcutaneously into the deltoid muscle of the upper arm.

[0050] The first dose may be administered on day 0, followed by a second dose every three weeks at about day 21, about day 42, about day 63, etc. Alternatively, the first dose may be administered on day 0, followed by a second dose every four weeks at about day 28, about day 56, about day 84, etc.

[0051] In some embodiments, the effective second dose is administered every two weeks after the first dose. In other embodiments, the effective second dose is administered every three weeks after the first dose. In another embodiment, the effective second dose is administered every four weeks after the first dose. In another embodiment, the effective second dose is administered every five weeks after the first dose. In another embodiment, the effective second dose is administered every six weeks after the first dose.

[0052] The first dose administered in the methods disclosed herein can be, for example, about 25 ng / kg, about 30 ng / kg, about 35 ng / kg, about 40 ng / kg, about 45 ng / kg, about 50 ng / kg, about 55 ng / kg, about 60 ng / kg, about 65 ng / kg, about 70 ng / kg, about 75 ng / kg, about 80 ng / kg, about 85 ng / kg, about 90 ng / kg, about 95 ng / kg, about 100 ng / kg, about 105 ng / kg, about 110 ng / kg, about 115 ng / kg, about 120 ng / kg, about 125 ng / kg, about 130 ng / kg, about 135 ng / kg, about 140 ng / kg, about 150 ng / kg, about 160 ng / kg, about 170 ng / kg, about 180 ng / kg, about 190 ng / kg, about 210 ng / kg, about 220 ng / kg, about 230 ng / kg, about 240 ng / kg, about 250 ng / kg, about 260 ng / kg, about 270 ng / kg, about 280 ng / kg, about 290 ng / kg, about 300 ng / kg, about 310 ng / kg, about 320 ng / kg, about 330 ng / kg, about 340 ng / kg, about 350 ng / kg, about 360 ng / kg, about 370 ng / kg, about 380 ng / kg, about 390 ng / kg, about 400 ng / kg, about 410 ng / kg, about 420 ng / kg, about ng / kg, about 145ng / kg, about 150ng / kg, about 155ng / kg, about 160ng / kg, about 165ng / kg, about 170ng / kg, about 175ng / kg, about 180ng / kg, about 185ng / kg, about 190ng / kg, about 195ng / kg, about 200ng / k g, about 205ng / kg, about 210ng / kg, about 215ng / kg, about 220ng / kg, about 225ng / kg, about 230ng / kg, about 235ng / kg, about 240ng / kg, about 245ng / kg, about 250ng / kg, about 255ng / kg, about 260ng / kg, about 26 5ng / kg, about 270ng / kg, about 275ng / kg, about 280ng / kg, about 285ng / kg, about 290ng / kg, about 295ng / kg, about 300ng / kg, about 305ng / kg, about 310ng / kg, about 315ng / kg, about 320ng / kg, about 325ng / kg kg, about 330ng / kg, about 335ng / kg, about 340ng / kg, about 345ng / kg, about 350ng / kg, about 355ng / kg, about 360ng / kg, about 365ng / kg, about 370ng / kg, about 375ng / kg, about 380ng / kg, about 385ng / kg, about 390ng / kg, approximately 395ng / kg, approximately 400ng / kg, approximately 405ng / kg, approximately 410ng / kg, approximately 415ng / kg, approximately 420ng / kg, approximately 425ng / kg, approximately 430ng / kg, approximately 435ng / kg, approximately 440ng / kg, approximately 445ng / kg, approximately 450n g / kg, about 455ng / kg, about 460ng / kg, about 465ng / kg, about 470ng / kg, about 475ng / kg, about 480ng / kg, about 485ng / kg, about 490ng / kg, about 495ng / kg, about 500ng / kg, about 505ng / kg, about 510ng / kg,Approximately 515ng / kg, approximately 520ng / kg, approximately 525ng / kg, approximately 530ng / kg, approximately 535ng / kg, approximately 540ng / kg, approximately 545ng / kg, approximately 550ng / kg, approximately 555ng / kg, approximately 560ng / kg, approximately 565ng / kg, approximately 570ng / kg, approximately 575ng / k g, approx. 580 ng / kg, approx. 585 ng / kg, approx. 590 ng / kg, approx. 595 ng / kg, approx. 600 ng / kg, approx. 605 ng / kg, approx. 610 ng / kg, approx. The first dose may be about 25 ng / kg to about 750 ng / kg, including about 645 ng / kg, about 650 ng / kg, about 655 ng / kg, about 660 ng / kg, about 665 ng / kg, about 670 ng / kg, about 675 ng / kg, about 680 ng / kg, about 685 ng / kg, about 690 ng / kg, about 695 ng / kg, about 700 ng / kg, about 705 ng / kg, about 710 ng / kg, about 715 ng / kg, about 720 ng / kg, about 725 ng / kg, about 730 ng / kg, about 735 ng / kg, about 740 ng / kg, about 745 ng / kg, and about 750 ng / kg. In one embodiment, the first dose is about 150 ng / kg.

[0053] The second dose administered in the methods disclosed herein can be, for example, about 50 ng / kg, about 55 ng / kg, about 60 ng / kg, about 65 ng / kg, about 70 ng / kg, about 75 ng / kg, about 80 ng / kg, about 85 ng / kg, about 90 ng / kg, about 95 ng / kg, about 100 ng / kg, about 105 ng / kg, about 110 ng / kg, about 115 ng / kg, about 120 ng / kg, about 125 ng / kg, about 130 ng / kg, about 135 ng / kg, about 140 ng / kg, about 145 ng / kg, about 150 ng / kg, about 155 ng / kg, about 160 ng / kg, Approximately 165ng / kg, approximately 170ng / kg, approximately 175ng / kg, approximately 180ng / kg, approximately 185ng / kg, approximately 190ng / kg, approximately 195ng / kg, approximately 200ng / kg, approximately 205ng / kg, approximately 210ng / kg, approximately 215ng / kg, approximately 220ng / kg, approximately 225n g / kg, about 230ng / kg, about 235ng / kg, about 240ng / kg, about 245ng / kg, about 250ng / kg, about 255ng / kg, about 260ng / kg, about 265ng / kg, about 270ng / kg, about 275ng / kg, about 280ng / kg, about 285ng / kg, Approximately 290ng / kg, approximately 295ng / kg, approximately 300ng / kg, approximately 305ng / kg, approximately 310ng / kg, approximately 315ng / kg, approximately 320ng / kg, approximately 325ng / kg, approximately 330ng / kg, approximately 335ng / kg, approximately 340ng / kg, approximately 345ng / kg, approximately 350n g / kg, about 355ng / kg, about 360ng / kg, about 365ng / kg, about 370ng / kg, about 375ng / kg, about 380ng / kg, about 385ng / kg, about 390ng / kg, about 395ng / kg, about 400ng / kg, about 405ng / kg, about 410ng / kg, Approximately 415ng / kg, approximately 420ng / kg, approximately 425ng / kg, approximately 430ng / kg, approximately 435ng / kg, approximately 440ng / kg, approximately 445ng / kg, approximately 450ng / kg, approximately 455ng / kg, approximately 460ng / kg, approximately 465ng / kg, approximately 470ng / kg, approximately 475n g / kg, about 480ng / kg, about 485ng / kg, about 490ng / kg, about 495ng / kg, about 500ng / kg, about 505ng / kg, about 510ng / kg, about 515ng / kg, about 520ng / kg, about 525ng / kg, about 530ng / kg, about 535ng / kg,Approximately 540 ng / kg, approximately 545 ng / kg, approximately 550 ng / kg, approximately 555 ng / kg, approximately 560 ng / kg, approximately 565 ng / kg, approximately 570 ng / kg, approximately 575 ng / kg, approximately 580 ng / kg, approximately 585 ng / kg, approximately 590 ng / kg, approximately 595 ng / kg, approximately 600 ng / kg, approximately 605 ng / kg, approximately 610 ng / kg, approximately 615 ng / kg, approximately 620 ng / kg, approximately 625 ng / kg, approximately 630 ng / kg, approximately 635 ng / kg, approximately 640 ng / kg, approximately 645 ng / kg, approximately 650 ng / kg, approximately 655 ng / kg, approximately 660 ng / kg g, approximately 665 ng / kg, approximately 670 ng / kg, approximately 675 ng / kg, approximately 680 ng / kg, approximately 685 ng / kg, approximately 690 ng / kg, approximately 695 ng / kg, approximately 700 ng / kg, approximately 705 ng / kg, approximately 710 ng / kg, approximately 715 ng / kg, approximately 720 ng / kg, approximately 725 ng / kg, approximately 730 ng / kg, approximately 735 ng / kg, approximately 740 ng / kg, approximately 745 ng / kg, approximately 750 ng / kg, approximately 755 ng / kg, approximately 760 ng / kg, approximately 765 ng / kg, approximately 770 ng / kg, approximately 775 ng / kg, approximately 780 ng / kg, approximately 785 ng / kg kg, approximately 790 ng / kg, approximately 795 ng / kg, approximately 800 ng / kg, approximately 805 ng / kg, approximately 810 ng / kg, approximately 815 ng / kg, approximately 820 ng / kg, approximately 825 ng / kg, approximately 830 ng / kg, approximately 835 ng / kg, approximately 840 ng / kg, approximately 845 ng / kg, approximately 850 ng / kg, approximately 855 ng / kg, approximately 860 ng / kg, approximately 865 ng / kg, approximately 870 ng / kg, approximately 875 ng / kg, approximately 880 ng / kg, approximately 885 ng / kg, approximately 890 ng / kg, approximately 895 ng / kg, approximately 900 ng / kg, approximately 905 ng / kg, approximately 910 ng / kg g / kg, approximately 915 ng / kg, approximately 920 ng / kg, approximately 925 ng / kg, approximately 930 ng / kg, approximately 935 ng / kg, approximately 940 ng / kg, approximately 945 ng / kg, approximately 950 ng / kg, approximately 955 ng / kg, approximately 960 ng / kg, approximately 965 ng / kg, approximately 970 ng / kg, approximately 975 ng / kg, approximately 980 ng / kg, approximately 985 ng / kg, approximately 990 ng / kg, approximately 995 ng / kg, approximately 1.00 μg / kg, approximately 1.05 μg / kg, approximately 1.1 μg / kg, approximately 1.15 μg / kg, approximately 1.2 μg / kg, approximately 1.25 μg / kg, approximately 1.3 μg / kg,It may be about 50 ng / kg to about 1.5 μg / kg, including about 1.35 μg / kg, about 1.4 μg / kg, about 1.45 μg / kg, and about 1.5 μg / kg.

[0054] In one embodiment, the second dose is about 300 ng / kg, hi one embodiment, the second dose is about 540 ng / kg, hi one embodiment, the second dose is about 750 ng / kg.

[0055] The second dose and subsequent doses (maintenance doses) may be administered to a subject in need thereof for 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or more.

[0056] The dosing regimens disclosed herein advantageously achieve clinical or partial clinical responses in solid tumors in human patients. Responses in solid tumors can be evaluated using RECIST v1.1 criteria. A complete response (CR) is characterized by the disappearance of all target lesions or the absence of ongoing evidence of disease. In addition, any pathological lymph nodes (whether target or non-target) must have a short axis reduction of <10 mm. A partial response (PR) is characterized by at least a 30% reduction in the sum of the diameters of target lesions, based on the baseline sum of the diameters.

[0057] In addition, in some embodiments, the administration regimen disclosed herein can surprisingly achieve clinical response of non-target lesions.Complete response (CR) of non-target lesions is characterized by the disappearance of all non-target lesions and normalization of tumor marker levels.In addition, all lymph nodes must be non-pathological in size (short axis of <10 mm).

[0058] V. Pharmaceutical Preparations In another aspect, provided herein is a therapeutic composition comprising an IL-12 ABD fusion protein and a carrier. The subject therapeutic compositions used in practicing the aforementioned methods can be formulated into pharmaceutical compositions containing a carrier suitable for the desired delivery method. Suitable carriers include any material that, when combined with the therapeutic composition, retains the anti-tumor function of the therapeutic composition and is generally non-reactive with the patient's immune system. Examples include, but are not limited to, any of several standard pharmaceutical carriers, such as sterile phosphate-buffered saline, bacteriostatic water, etc. (See generally, Remington's Pharmaceutical Sciences 16th Edition, A. Osal., Ed., 1980).

[0059] Formulations of albumin binding domain (ABD) polypeptides used in accordance with the present invention are prepared for storage by mixing the ABD polypeptide having the desired purity, in the form of a lyophilized formulation or aqueous solution, with optional pharmaceutically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.

[1980] ). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol), low molecular weight (fewer than about 10 residues) polypeptides; serum albumin, gelatin, or the like. or proteins such as immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA or DPTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; counterions that form salts, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0060] The formulations herein may also contain multiple active compounds as needed for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide multivalent interleukin polypeptides with different specificities. Alternatively, or in addition, the compositions may include cytotoxic agents, cytokines, growth inhibitory agents, and / or small molecule antagonists. Such molecules are suitably present in combination in amounts effective for the intended purpose.

[0061] The active ingredient may also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacylate) microcapsules, prepared by, for example, coacervation techniques or by interfacial polycondensation, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0062] Formulations to be used for in vivo administration should be sterile or nearly sterile, which is readily accomplished by filtration through sterile filtration membranes.

[0063] Sustained-release preparations may also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing antibodies, which matrices are in the form of shaped articles, such as films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. Polymers such as ethylene vinyl acetate and lactic acid-glycolic acid allow the release of molecules for over 100 days, while certain hydrogels release proteins for shorter periods.

[0064] If encapsulated albumin-binding domain polypeptides remain in the body for extended periods, they may denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is found to be intermolecular S--S bond formation via thio-disulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solution, controlling water content, using appropriate additives, and developing specific polymer matrix compositions. [Example]

[0065] The following examples are provided to illustrate the present invention and are not intended to limit the invention to any particular application or theory of operation. Example 1: A Phase I Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SON-1010 (IL-12-FHAB) in Adult Patients with Advanced Solid Tumors

[0066] Clinical trial overview We will conduct a Phase I clinical trial (first-in-human, non-randomized, open-label, adaptive design, outpatient) to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of SON-1010 administered as a subcutaneous (SC) dose every 14 to 28 days to patients with advanced solid tumors. The study will utilize a traditional 3+3 dose escalation design to establish a recommended Phase II dose (RP2D) and / or maximum tolerated dose (MTD) in up to five dose escalation arms and to extend the dataset at the recommended RP2D. A summary of the objectives and endpoints is provided in Table 2. The planned dose escalation schedule for the five dose escalation arms is provided in Table 3.

[0067] Approximately 36 patients will be enrolled in total: 6 patients per cohort at five dose levels (1-6 patients per cohort) for a total of up to 30 patients during dose escalation, and an additional 6 patients (or 9 patients if only 3 patients were studied upfront) at the RP2D and MTD as expansion arms (12 patients total at that dose). Patients are considered enrolled if they agree to participate in the study after completing the informed consent process and are accepted into the study. Potential patients who are screened for purposes of trial eligibility but do not participate in the trial are not considered enrolled unless otherwise specified.

[0068] Patients will receive SON-1010 in 14- to 28-day treatment cycles for up to two years until discontinuation due to disease progression or adverse events (AEs), but the study may be extended beyond that period based on patient factors, accumulated drug data, potential regulatory approval for commercial use, and drug availability. If nonlinear PK is observed at any dose level, PK and PD samples from all prior cohorts may be used for interim PK and PD analyses to select one or the other dose level escalation and timing, or intermediate doses may be included for up to two additional cohorts.

[0069] The overall response rate at each dose level will be determined using RECIST v1.1 guidelines for measurable, non-measurable, target, and non-target lesions, and objective tumor response criteria (complete response [CR], partial response [PR], stable disease [SD], or progressive disease). In addition, serum and urine levels of SON-1010 will be assessed with a commercially available enzyme-linked immunosorbent assay for IL-12. Table 2: Objectives and endpoints [Table 2-1] [Table 2-2] Table 3: Planned dose escalation schedule [Table 3]

[0070] Detailed test design Once four baseline PK (and a single baseline PD) samples were obtained, the first patient in Cohort 1 received the lowest planned dose of SON-1010 (0.05 μg / kg) for one week as a sentinel patient. A total of three patients were treated with that dose of SON-1010 and observed for at least seven days after the second dose (dose-limiting toxicity (DLT) observation period consisting of cycle 1 day 1 (C1D1) through cycle 2 day 8 (C2D8)) before enrolling in the next cohort. In the event that a patient in any cohort experienced a DLT, the design included enrollment of up to six patients at that dose level.

[0071] In the first two 3-patient dose escalation cohorts, one patient will be treated and observed for safety (as a sentinel subject) until cycle 1 day 5 (C1D5) before treating additional patients in that cohort. Once all patients in a cohort have received two doses of SON-1010 and completed the 35-day (DLT observation period), dose escalation to subsequent cohorts may proceed. Subsequent cohorts after dosing at M1 are planned at the doses shown in Table 3. Intermediate dose levels may be further expanded in consultation with the SRC, but dose levels below M1 will not be evaluated.

[0072] If no DLTs are reported during the DLT period at any given dose level, patient enrollment can proceed to the next dose level. Cohorts with one DLT during the DLT period are expanded to include six patients. If two or more patients in any cohort experience a DLT during the DLT period, patient enrollment at that dose is halted and the lower dose cohort is expanded to six patients. The lower dose level for this cohort may be the previous lower dose (if six patients have not yet enrolled at that lower dose), or an intermediate dose level may be evaluated.

[0073] During dose escalation, with sponsor approval, additional patients may be enrolled at the previously approved dose to further explore safety and tolerability. Adverse events occurring in these patients will not be considered evaluable for the DLT definition, but the SRC may consider these AEs when determining the RP2D for the expansion phase. Table 4 provides the criteria for dose escalation of SON-1010. Table 4: Dose Escalation Criteria for SON-1010 [Table 4]

[0074] Eligibility Criteria Patients are eligible to participate in the study if all of the following criteria apply: 1. Age ≥ 18 years at the time of informed consent 2. Patients must have histologically or cytologically verified solid epithelial or mesenchymal tumors. 3. Locally advanced or metastatic disease 4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or, where appropriate, modified criteria for immunotherapy (referred to as iRECIST). Lesions located in previously irradiated areas are considered measurable if progression is documented in such lesions. 5. Have been treated with standard treatment for the disease and have no alternative standard treatments that are deemed by the treating physician to provide reasonable or potentially better benefit, or are not candidates for standard treatment for the disease due to underlying physical conditions. Note that if alternative therapies known to provide clinical benefit are available to the patient, the patient should be informed of these therapies during the informed consent process. 6. Subjects must weigh >50 kg to ≤120 kg at screening (to facilitate dilution of SON-1010 prior to administration). 7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 8. Adequate organ and bone marrow function as defined by the following laboratory parameters by Day -1 in the absence of growth factors: Hematological: Neutrophils ≥ 1500 / μL, platelets ≥ 100,000 / μL, lymphocytes ≥ 500 / μL, hemoglobin ≥ 9 g / dL (blood transfusion and / or erythropoietin within 2 weeks prior to blood collection are not permitted) b. Kidneys: Estimated glomerular filtration rate ≥ 45 mL / min / 1.73 m2 (Levey 2009) c. Liver: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN (if liver metastases); international normalized coagulation ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN; serum total bilirubin ≤1.5 × ULN or total bilirubin ≤ULN (for patients with total bilirubin >1.5 × ULN) (excluding elevated bilirubin secondary to Gilbert disease). Confirmation of the Gilbert diagnosis requires elevated unconjugated (indirect) bilirubin; normal complete blood count (for the past 12 months), blood smear, and reticulocyte count; and normal transaminases and alkaline phosphatase for the past 12 months. d. Chemistry: Albumin ≥ 3.0 g / dL at screening 9. Women of childbearing potential who are postmenopausal <1 year but not permanently infertile must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-HCG]) at baseline (unless they have had a hysterectomy) and agree to use two highly effective methods of birth control throughout the study and for 30 days after the final dose of study intervention. Women of no childbearing potential (those who have had a tubal ligation, hysterectomy, or bilateral oophorectomy or are postmenopausal ≥1 year) or whose partners have undergone a vasectomy are not required to use contraception. No childbearing potential is defined as surgically infertile or postmenopausal (defined as 12 months of spontaneous amenorrhea). A follicle-stimulating hormone (FSH) level >40 IU / L at screening confirms postmenopausal status. If a patient is not sexually active but will become active, she and her male partner must use two appropriate methods of contraception. 10. Men and their female partners must use highly effective methods of birth control if the female partner(s) are of fertile potential and must not donate sperm during the study and for 30 days after the last dose of study intervention. Contraceptive guidance is provided in Section 10.4. 11. Willing and able to sign the informed consent described in Section 10.1.3, including compliance with the requirements and regulations listed in the Informed Consent Form (ICF) and this protocol. 12. Must be able to communicate effectively with investigator and / or site personnel and comply with overall study requirements.

[0075] Exclusion criteria Patients will be excluded from the study if any of the following criteria apply: 1. Subjects with a history of allergy to any component of the study intervention. 2. Anyone with a history of severe allergic / anaphylactic reactions. 3. Subjects with HIV-1 or HIV-2 infection or a history of Kaposi's sarcoma and / or multicentric Castleman disease. 4. Currently active liver disease from any cause, including hepatitis A (hepatitis A virus IgM positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with undetectable viral HCV after treatment are eligible (Note: Patients must have completed curative antiviral therapy at least 4 weeks prior to screening). 5. Pregnant and / or breastfeeding individuals 6. Receipt of a live or live-attenuated vaccine within 28 days prior to the first dose of the study intervention. Note: Killed vaccines that are not live or live-attenuated and COVID-19 vaccines are permitted if administered >14 days prior to the first dose. 7. History of any active infection requiring systemic antibiotic, antiviral, or antifungal therapy, including COVID-19, within 14 days prior to the first dose of study intervention, as determined by currently recommended study strategies for acute infections. 8. Any acute non-infectious illness that has not resolved within 14 days prior to Day 1. 9. Anyone with a history of, known, or suspected autoimmune disease (Exception(s): Patients who are clinically euthyroid at screening, have vitiligo, type 1 diabetes, resolved infantile atopic dermatitis, hypothyroidism, or hyperthyroidism are permitted). Other exceptions may be made after consultation with the Sponsor Medical Monitor for patients who have not been treated for an autoimmune disorder within the past three years. 10. Active central nervous system metastases and / or carcinomatous meningitis. Patients who have previously been treated for brain metastases may participate, provided they are clinically stable for at least 4 weeks prior to study enrollment and have no evidence of new or expanding brain metastases. 11. If currently on treatment and clinically euthyroid, have not recovered from toxicity from prior anticancer therapy, defined as not resolved to baseline or Grade 1 per CTCAE V 5.0 criteria (NCI 2017), excluding alopecia, peripheral neuropathy, and hypothyroidism secondary to prior checkpoint inhibitor therapy. 12. Received any investigational drug or treatment within 5 half-lives (or 28 days, whichever is shorter) prior to the first dose of the study intervention. 13. Has received any prior immunotherapy or checkpoint inhibitor treatment within 5 half-lives (or 3 months, whichever is shorter) of the last dose of treatment (unless approved by the sponsor). 14. Use of systemic steroids prednisone (or equivalent) >10 mg / day within 14 days of enrollment, excluding use of topical (topical, nasal, or inhaled) steroids. Restricted systemic steroid use (e.g., in patients with exacerbated reactive airway disease) must be completed at least 10 days prior to enrollment. Use of steroids to prevent IV contrast allergic reactions or anaphylaxis in patients with a known contrast allergy is permitted at any time prior to enrollment. 15. Subjects with active secondary malignancies, except for any of the following: Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or stage 0 carcinoma in situ Adequately treated stage I cancer in which the patient is currently in remission and has been in remission for ≥ 2 years Low-risk prostate cancer with a Gleason score of <7 and a prostate-specific antigen level of <10 ng / mL Any other cancer from which the patient has been disease-free for ≥ 2 years 16. Individuals who use biotin (i.e., vitamin B7) or biotin-containing supplements at a dose greater than the appropriate daily intake of 30 μg (FDA 2019) (Note: Patients switching from a high dose to a dose of 30 μg / day or less are eligible). 17. Subject has had any of the following events within the 6 months prior to Baseline Day 1: Myocardial infarction Unstable angina Unstable and symptomatic ischemic heart disease New York Heart Association Class III or IV heart failure Thromboembolic events (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease) 18. Heart rate-corrected QT interval (QTc) on electrocardiogram >470 milliseconds, as measured by the Fridericia formula [QTcF=QT / (RR0.33)]. Patients with pacemakers or bundle branch block who have prolonged QTc may be enrolled in this study if confirmed by medical monitoring. Preliminary results Preliminary results showing cytokine response levels in individuals from cohorts 1 and 2 are presented in Figure 3. Acute inflammation was assessed using a multi-analyte Luminex bead assay in studies SB101 and SB102. IL-12p70, used to measure SON-1010, showed prolonged pharmacokinetics and a controlled, dose-dependent increase in IFNγ. There was no evidence of cytokine release syndrome (CRS). IL-1β, IL-6, and IL-8 signals were also minimal to zero, while IL-10 was induced at low levels. In addition, Figure 4 provides preliminary efficacy results for cohorts M1, M2, and M3. One patient is stable, showing disappearance of target tumor and ascites. Two patients who had PD at enrollment have SD. Example 2: Proof-of-Concept Study to Evaluate the Combination of SON-1010 (IL-12-FHAB) and Anti-PD-L1 Antibody (Zimberelimab) in Patients with Platinum-Resistant Ovarian Cancer

[0076] Clinical trial overview This multicenter, two-part Phase Ib / IIa dose-escalation study will evaluate the safety, tolerability, PD, and efficacy of SON-1010 administered subcutaneously (SC) alone or in combination with an intravenously (IV) anti-PD-L1 antibody (zimberelimab). Part 1 will utilize a traditional 3+3 dose-escalation design to establish the recommended Phase II dose (RP2D) and / or maximum tolerated dose (MTD) of SON-1010 in combination with zimberelimab in patients with advanced solid tumors across up to five dose-escalation arms, and will extend the data set at the recommended RP2D. Part 2 will evaluate the efficacy of SON-1010 alone or in combination with standard of care (SOC) in patients with platinum-resistant ovarian cancer (PROC) using the MTD as one of three randomized arms, with the goal of establishing proof of concept (POC).

[0077] The MTD is defined as the highest dose of SON-1010 that does not cause two or more DLTs in a cohort of six patients. The RP2D will be the MTD unless: significant clinical anti-tumor effect (such as complete response [CR], partial response [PR], or stable disease for ≥ 4 months) is nonlinear or occurs below the MTD, in which case the clinically active dose level may be selected as the RP2D; or toxicity observed beyond cycle 1 requires reducing the RP2D below the MTD level; or the MTD is not achieved, in which case the highest dose level administered may be the RP2D, or the lowest dose level achieving maximum pharmacodynamic activity can be considered.

[0078] The dosing strategy for this study will utilize a desensitizing first dose, preferably 150 ng / kg, of SON-1010, followed by potentially higher maintenance doses to minimize toxicity and improve the likelihood of reaching a therapeutic dose of SON-1010. A summary of the objectives and endpoints is provided in Table 5.

[0079] Part 1 data will be summarized by dose cohort, expansion cohort, and overall patient population. All assessments prior to the first dose of study drug will be considered baseline. If there are multiple baseline assessments, the most recent assessment will be used for statistical analysis. No formal hypothesis testing of safety or PD parameters is planned.

[0080] In Part 2 of the study, patients will be assigned in a 1:1:1 ratio to each of the three treatment arms using an automated central randomization method. Randomization will be stratified based on: Disease stage and weight loss status at diagnosis Stage III and maximum residual disease diameter ≤ 1 cm Stage III and maximum residual disease diameter >1 cm Stage IV Determine whether the subject is experiencing: First or second recurrence Third or more recurrences Table 5: Objectives and endpoints [Table 5]

[0081] Part 1: Dose escalation Dose escalation will be performed in Part 1 in patients with advanced solid tumors based on the planned dose escalation schedule provided in Table 6. A total of approximately 36 patients will be included (30 patients during dose escalation and 6 patients during RP2D / MTD expansion). Up to 12 additional patients in up to two intermediate dose level cohorts may be accrued.

[0082] The first (sentinel) patient in Cohort C1 will receive a desensitizing dose of SON-1010 combined with a fixed dose of zimblerimab (360 mg), followed by a maintenance dose of SON-1010 with zimblerimab every 3 weeks. Patients will be treated and observed for 7 days before enrolling additional patients in that cohort. Each cohort will be treated and observed for at least 28 days (dose-limiting toxicity (DLT) observation period), consisting of Day 1 of Cycle 1 (C1D1) through Day 8 of Cycle 2 (C2D8). A Trial Steering Committee (TSC) will then meet to discuss the results of each cohort in Part 1 before enrolling the next cohort. Efficacy will be tracked by CA125 levels (Rustin 2011) and RECIST v1.1 scores (Eisenhauer 2009) every 2 months until progression or discontinuation criteria are met. If the patient is clinically stable and the PI chooses to continue, iRECIST rules can be followed until progression is confirmed (Seymour 2017). Table 6: Planned SON-1010 dose escalation schedule for Part 1 [Table 6]

[0083] If no DLTs are reported during the DLT period at a given dose level, patient enrollment can proceed to the next dose level. Cohorts with one DLT during the DLT period are expanded to six patients. If two or more patients in any cohort experience a DLT during the DLT period, patient enrollment at that dose is halted, and the lower dose cohort is expanded to six patients. The lower dose level for this cohort may be the previous lower dose (if six patients have not yet enrolled at that lower dose), or an intermediate dose level may be evaluated. If fewer than two DLTs are observed in six patients at this lower dose, this lower dose is considered the MTD, and the most effective cohort is expanded to 12 patients to establish the RP2D.

[0084] Dose escalation to subsequent cohorts will be based on the dose escalation schema described in Table 7, and all patients in a cohort may proceed once they have received two combination doses and completed 28 days. Subsequent cohorts after C1 administration will be planned at the doses shown in Table 6. During dose escalation, with sponsor approval, additional patients may be enrolled at previously approved doses to further explore safety and tolerability. Adverse events occurring in these patients will not be considered evaluable for the DLT definition, but the TSC may consider these AEs when determining the RP2D for the expansion phase. Table 7: Decision Schema for a Phase I Dose-Escalation Study of SON-1010 [Table 7]

[0085] SON-1010 will be administered as a single SC dose with a fixed dose of 360 mg IV zimberelimab in each treatment cycle (21 days) (maximum of 35 cycles). Patients will receive SON-1010 and zimberelimab at the cohort dose level until disease progression or discontinuation due to an AE. Up to five dose-level cohorts, each containing 3-6 patients, are planned, totaling approximately 30 patients during dose escalation (Table 6). Enrollment of 6-9 patients at RP2D / MTD (total of 12 patients at that dose) is also planned as an expansion group.

[0086] Samples for PD will be collected at several time points during the first two cycles of Part 1 of the study to assess the presence and effect of SON-1010 after single and multiple doses. Key PD parameters include IFNγ, IL1β, IL2, IL4, IL6, IL8, IL10, IL12p70, IL13, and TNFα. Part 2: Proof of Concept

[0087] Once the RP2D of SON-1010 in combination with zimberelimab is determined in Part 1, patients with a PROC may be randomized 1:1:1 to one of three arms (R1-R3) in Part 2: R1: SON-1010 alone at the RP2D dose of SON-1010 from Example 1 R2: SON-1010 in combination with zimberelimab at the RP2D dose of SON-1010 from Part 1 · R3: Standard treatment (PI decision on choice of chemotherapy).

[0088] Approximately 40 patients with recurrent PROC will be included in each group, for a total of 120 patients. SON-1010 will be administered as a single SC dose with a fixed dose of 360 mg IV zimblerimab during each treatment cycle (21 days) in groups C1-C5, R1, and R2 (maximum of 35 cycles). SC doses will be injected alternately in the upper arms above the deltoid muscle, or in the thigh (preferred) or abdomen if previous surgery prevents use of the arm. Zimberelimab will be administered IV every 21 days in group R2. Patients in group R3 will be administered according to the SOC selected by the PI.

[0089] Study participation is expected to average approximately seven months, including screening, assuming an average of eight doses per patient. Treatment will be supported for up to two years but may be extended beyond that period based on patient factors, accumulated drug data, potential regulatory approval for commercial use, and drug availability. The primary clinical efficacy endpoint in Part 2 will be PFS (including any death), with disease progression determined primarily according to RECIST v1.1 criteria. Eligibility Criteria

[0090] Individuals eligible to participate in the study must meet the following criteria: 1. Age ≥ 18 years at the time of informed consent 2. Part 1: Participants must have histologically or cytologically verified solid tumors, and patients must have locally advanced or metastatic disease. They must have been treated with standard therapy for their disease and have no alternative standard treatment options deemed by the treating physician to offer reasonable or potentially better benefit. Part 2: Participants must have platinum-resistant ovarian cancer (defined as at least a partial response to a platinum-containing regimen and recurrence within 6 months of completion), including epithelial, fallopian tube, or peritoneal cancer. Subjects with platinum-refractory ovarian cancer are eligible, provided the outcome is directed at a second or subsequent repeat platinum regimen (i.e., not during the first regimen). Refractory disease is defined as failure to achieve at least partial response to a platinum-containing regimen (i.e., SD or actual disease progression). Subjects may have received one or more alternative regimens prior to this study, including maintenance therapy between successive treatments. 3. Part 2: Documented histological diagnosis of cancer is required, and the following subtypes are eligible: high-grade (grade ≥ 3+) serous carcinoma; low-grade serous carcinoma; endometrioid, clear cell, or mucinous ovarian adenocarcinoma; poorly differentiated adenocarcinoma; or mixed (including the above subtypes). Note that synchronous serous or endometrioid uterine carcinoma or fallopian carcinoma are acceptable. 4. Locally advanced or metastatic disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or (for PROC) with CA125 levels >2-fold above the ULN. Lesions located in previously irradiated areas are considered measurable if progression is documented in such lesions. 5. Must weigh >50 kg and ≤120 kg at screening (to facilitate SON-1010 dilution prior to administration). 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 7. Adequate organ and bone marrow function in the absence of growth factors as defined by the following laboratory parameters: [Table 8-1] [Table 8-2] 8. Women of childbearing potential who are postmenopausal <1 year and not permanently infertile must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-HCG]) at baseline and must agree to use two highly effective methods of birth control during the study and for 30 days after the last dose of study intervention. Women of no childbearing potential (who have had a tubal ligation, hysterectomy, or bilateral oophorectomy, or are postmenopausal ≥1 year) or whose partners have had a vasectomy are not required to use any contraceptive method. Contraceptive methods appropriate for participants include: Condoms with spermicidal gel Diaphragm with spermicidal gel Coil (intrauterine device) Oral contraceptives Depot progesterone injections Progesterone implants (e.g., Implanon®) NuvaRing (registered trademark) Ortho Evra® Not of childbearing potential is defined as surgically sterile (confirmed hysterectomy, tubal ligation, or bilateral salpingo-oophorectomy) or postmenopausal (defined as 12 months of spontaneous amenorrhea). A follicle-stimulating hormone (FSH) level >35 IU / L was performed at screening to confirm status. If a participant is not sexually active but becomes active, she and her male partner must use two adequate methods of contraception. 9. Men and their female partners must use highly effective birth control methods if the female partner(s) are fertile and must not donate sperm during the study and for 30 days after the final dose of study intervention. 10. Willing and able to sign the informed consent form, including the Informed Consent Form (ICF) and compliance with the requirements and regulations listed in this protocol.

[0091] Exclusion criteria Individuals who meet any of the following exclusion criteria are ineligible to participate in this study: 1. Subjects with a history of allergy to any component of the study intervention or a history of severe allergic / anaphylactic reactions. 2. Persons who have been hospitalized due to subacute intestinal obstruction within 28 days prior to C1D1. 3. Individuals infected with HIV-1 or HIV-2 and with a history of Kaposi's sarcoma and / or multicentric Castleman disease. 4. Currently active liver disease from any cause, including hepatitis A (hepatitis A virus IgM positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with undetectable HCV virus after treatment are eligible (Note: Patients must have completed curative antiviral therapy at least 4 weeks prior to screening). Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative (Note: Patients must have been on HBV antiviral therapy for at least 4 weeks prior to screening). 5. Pregnant and / or breastfeeding individuals 6. Receipt of a live or live-attenuated vaccine within 30 days prior to the first dose of the study intervention. (Note: Receipt of killed vaccines that are not live or live-attenuated and COVID-19 vaccines is permitted if received >14 days.) 7. History of any active infection requiring systemic antibiotic, antiviral, or antifungal therapy, including COVID-19, within 14 days prior to the first dose of study intervention. 8. Any acute non-infectious illness that has not resolved within 14 days prior to Day 1. 9. Anyone with a history of, known, or suspected autoimmune disease (Exception(s): Patients who are clinically euthyroid at screening, have vitiligo, type 1 diabetes, resolved infantile atopic dermatitis, hypothyroidism, or hyperthyroidism are permitted). Other exceptions may be made after consultation with the Sponsor Medical Monitor for patients who have not been treated for an autoimmune disorder within the past three years. 10. Active central nervous system metastases and / or carcinomatous meningitis. Patients who have previously been treated for brain metastases may participate, provided they are clinically stable for at least 4 weeks prior to study enrollment and have no evidence of new or expanding brain metastases. 11. If currently on treatment and clinically euthyroid, have not recovered from toxicity from prior anticancer therapy, defined as not recovering to baseline or Grade 1 (NCI 2017), excluding alopecia, peripheral neuropathy, and hypothyroidism secondary to prior checkpoint inhibitor therapy. 12. Received any investigational drug or treatment within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of the study intervention. 13. Has received any prior immunotherapy or checkpoint inhibitor treatment within 5 half-lives (or 3 months, whichever is shorter) of the last dose of treatment (unless approved by the sponsor). 14. Use of systemic steroids prednisone (or equivalent) >10 mg / day within 10 days of enrollment, excluding use of topical (topical, nasal, or inhaled) steroids. Restricted systemic steroid use (e.g., in patients with exacerbated reactive airway disease) must be completed at least 10 days prior to enrollment. Use of steroids to prevent IV contrast allergic reactions or anaphylaxis in patients with a known contrast allergy is permitted at any time prior to enrollment. 15. Subjects with active secondary malignancies, except for any of the following: Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix adequately treated stage I cancer in which the patient is currently in remission and has been in remission for ≥ 2 years; Low-risk prostate cancer with a Gleason score <7 and a prostate-specific antigen <10ng / mL, or Any other cancer from which the patient has been disease-free for ≥ 2 years. 16. Individuals who use biotin (i.e., vitamin B7) or biotin-containing supplements at a dose greater than the appropriate daily intake of 30 μg (FDA 2019). (Note: Patients switching from a high dose to a dose of 30 μg / day or less are eligible for study enrollment.) 17. Within 6 months prior to Baseline Day 1, subject has had any of the following: Myocardial infarction, Unstable angina, Unstable and symptomatic ischemic heart disease, New York Heart Association (NYHA) class III or IV heart failure, thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), any other significant cardiac disease (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease); Heart rate-corrected QT interval (QTc) on ECG >470 milliseconds, as measured by the Fridericia formula [QTcF=QT / (RR^0.33)]. Patients with pacemakers or bundle branch block who have prolonged QTc may be enrolled in the study if confirmed by medical monitoring.

[0092] Certain embodiments disclosed herein may be further limited in the claims using the language "consisting of" or "consisting essentially of." When used in a claim, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present disclosure so claimed are essentially or explicitly described and available herein.

[0093] Where numerical values ​​are given in the context of the present disclosure, those skilled in the art will understand that the technical effect of the feature in question is ensured within an interval of precision that typically encompasses a deviation of the given numerical value of ±10%, preferably ±5%. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques.

[0094] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight and median size, reaction conditions, and the like used in the specification and claims are to be understood as modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

[0095] As used in the context of describing this disclosure (particularly in the context of the claims below), the terms "a," "an," "the," and similar referents should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually listed herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better clarify the disclosure and does not pose a limitation on the scope of the disclosure as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[0096] Grouping of alternative elements or embodiments of the present disclosure disclosed herein is not to be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group, and thus fulfills the written description of all Markush groups used in the appended claims.

[0097] Certain embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations on these described embodiments will, of course, become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that such variations will be adopted by those skilled in the art as appropriate, and the inventors intend for the present disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0098] It should be understood that the embodiments of the present disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that may be employed are within the scope of the present disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that precisely as shown and described.

[0099] Although the present disclosure has been described and illustrated herein by reference to various specific materials, procedures, and examples, it is understood that the disclosure is not limited to the particular combination of materials and procedures selected for that purpose. Numerous variations of these details may be implied as will be understood by those skilled in the art. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the present disclosure being indicated by the following claims. All references, patents, and patent applications mentioned in this application are incorporated herein by reference in their entirety.

Claims

1. 1. A method for treating cancer in a subject in need thereof, comprising: The method comprises administering to the subject in need thereof an effective first dose of an IL-12 albumin binding domain (ABD) fusion protein, and, after administration of the first dose, administering an effective second dose of an IL-12 ABD fusion protein every three or four weeks, wherein the second dose is greater than the first dose.

2. 10. The method of claim 1, wherein the effective second and subsequent doses of IL-12 ABD fusion protein are administered every three weeks after administration of the first dose.

3. 10. The method of claim 1, wherein the effective second and subsequent doses of IL-12 ABD fusion protein are administered every four weeks after administration of the first dose.

4. 10. The method of claim 1, wherein the first dose is from about 25 ng / kg to about 750 ng / kg.

5. 5. The method of claim 4, wherein the first dose is about 150 ng / kg.

6. 10. The method of claim 1, wherein the second and subsequent doses are from about 50 ng / kg to about 1.5 μg / kg.

7. 7. The method of claim 6, wherein the second dose and subsequent doses are about 300 ng / kg.

8. 7. The method of claim 6, wherein the second dose and subsequent doses are about 540 ng / kg.

9. 7. The method of claim 6, wherein the second dose and subsequent doses are about 750 ng / kg.

10. 10. The method of claim 1, wherein the first dose and the second and subsequent doses are administered intravenously.

11. 10. The method of claim 1, wherein the first dose and the second and subsequent doses are administered subcutaneously.

12. 2. The method of claim 1, wherein the albumin binding domain of the IL-12 ABD fusion protein comprises a variable heavy chain domain comprising SEQ ID NO: 2, or a variant thereof, and a variable light chain domain comprising SEQ ID NO: 6, or a variant thereof.

13. The method of claim 12, wherein the albumin binding domain is an scFv comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof.

14. 14. The method of claim 13, wherein the IL-12 of the IL-12 fusion protein is a single-chain IL-12 comprising a p35 subunit covalently linked to a p40 subunit.

15. 15. The method of claim 14, wherein the p40 subunit has the amino acid sequence of SEQ ID NO: 12 or a variant thereof.

16. 16. The method of claim 14 or 15, wherein the p35 subunit has the amino acid sequence of SEQ ID NO: 13 or a variant thereof.

17. The method of any one of claims 14 to 16, wherein the single-chain IL-12 has the amino acid sequence of SEQ ID NO:

10.

18. The method of any one of claims 12 to 17, wherein the IL-12 ABD fusion protein has the amino acid sequence of SEQ ID NO:

11.

19. The method of claim 1 , wherein the subject is a human patient.

20. 20. The method of claim 19, wherein the human patient is an adult human patient.

21. The method of claim 1 , wherein the cancer is a solid tumor.

22. 22. The method of claim 21, wherein the solid tumor is a solid epithelial tumor or a mesenchymal tumor.

23. 10. The method of claim 1, further comprising administering a checkpoint inhibitor to the subject in need thereof.

24. 10. The method of claim 1, wherein the subject in need thereof has previously received standard treatment or is not a candidate for standard treatment.

25. 1. A method for achieving a clinical response or partial clinical response of a solid tumor in a human patient, comprising:

10. The method of claim 1, further comprising administering to the human patient an effective first dose of an IL-12 albumin binding domain (ABD) fusion protein and an effective second dose of an IL-12 ABD fusion protein every two, three, or four weeks after administration of the first dose, wherein the second dose is greater than the first dose.

26. 26. The method of claim 25, wherein the effective second and subsequent doses of IL-12 ABD fusion protein are administered every three weeks after administration of the first dose.

27. 26. The method of claim 25, wherein the effective second and subsequent doses of IL-12 ABD fusion protein are administered every four weeks after administration of the first dose.

28. 26. The method of claim 25, wherein the first dose is from about 25 ng / kg to about 750 ng / kg.

29. 29. The method of claim 28, wherein the first dose is about 150 ng / kg.

30. 26. The method of claim 25, wherein the second and subsequent doses are from about 50 ng / kg to about 1.5 μg / kg.

31. 31. The method of claim 30, wherein the second dose and subsequent doses are about 300 ng / kg.

32. 31. The method of claim 30, wherein the second dose and subsequent doses are about 540 ng / kg.

33. 31. The method of claim 30, wherein the second dose and subsequent doses are about 750 ng / kg.

34. 26. The method of claim 25, wherein the first dose and the second and subsequent doses are administered intravenously.

35. 26. The method of claim 25, wherein the first dose and the second and subsequent doses are administered subcutaneously.

36. 26. The method of claim 25, wherein the albumin binding domain of the IL-12 ABD fusion protein comprises a variable heavy chain domain comprising SEQ ID NO: 2, or a variant thereof, and a variable light chain domain comprising SEQ ID NO: 6, or a variant thereof.

37. 37. The method of claim 36, wherein the albumin binding domain is an scFv comprising the amino acid sequence of SEQ ID NO: 1 or a variant thereof.

38. 38. The method of claim 37, wherein the IL-12 of the IL-12 fusion protein is a single-chain IL-12 comprising a p35 subunit covalently linked to a p40 subunit.

39. 39. The method of claim 38, wherein the p40 subunit has the amino acid sequence of SEQ ID NO: 12 or a variant thereof.

40. 40. The method of claim 38 or 39, wherein the p35 subunit has the amino acid sequence of SEQ ID NO: 13 or a variant thereof.

41. The method of any one of claims 38 to 40, wherein the single-chain IL-12 has the amino acid sequence of SEQ ID NO:

10.

42. 42. The method of any one of claims 36 to 41, wherein the IL-12 ABD fusion protein has the amino acid sequence of SEQ ID NO:

11.

43. 26. The method of claim 25, wherein the solid tumor is a solid epithelial tumor or a mesenchymal tumor.

44. 26. The method of claim 25, further comprising administering a checkpoint inhibitor to a subject in need thereof.

Images