Methods of treating cancer with polyvalent sting activating compositions and PD-1 inhibitors

Abstract

Described herein are methods of treating cancer using therapeutic pH responsive compositions and anti-PD1 compositions.

Description

Attorney Docket No.100007_00059 METHODS OF TREATING CANCER WITH POLYVALENT STING ACTIVATING COMPOSITIONS AND PD-1 INHIBITORS

[0001] The Sequence Listing in an ASCII text file, named 100007_00058_SEQ_LISTING.xml of 9,772 bytes, created on August 29, 2025, and submitted to the United States Patent and Trademark Office via EFS-Web, is incorporated herein by reference. BACKGROUND OF THE INVENTION [0001.5] Multifunctional nanoparticles have received attention in a wide range of applications such as biosensors, diagnostic nanoprobes and targeted drug delivery systems. These efforts have been driven to a large extent by the need to improve biological specificity with reduced side effects in diagnosis and therapy through the precise, spatiotemporal control of agent delivery in various physiological systems. In order to achieve this goal, efforts have been dedicated to develop stimuli-responsive nanoplatforms. Environmental stimuli that have been exploited for pinpointing the delivery efficiency include pH, temperature, enzymatic expression, redox reaction and light induction. Among these activating signals, pH trigger is one of the most extensively studied stimuli based on two types of pH differences: (a) pathological (e.g. tumor) vs. normal tissues and (b) acidic intracellular compartments. For example, due to the unusual acidity of the tumor extracellular microenvironment (pH ~ 6.5), several pH-responsive nano systems have been reported to increase the efficacy of therapy.

[0002] The stimulator of interferon genes (STING) plays a central role in innate immunity during infection and cancer. STING is endogenously activated by 2’,3’-cyclic-GMP- AMP (cGAMP), a cyclic dinucleotide synthesized by cGAMP synthase (cGAS) in response to cytosolic DNA as a danger signal. Activation of STING mediates a multifaceted type Ⅰ interferon (IFN-Ⅰ) response that promotes the maturation and migration of dendritic cells, and primes cytotoxic T lymphocytes and nature killer cells for spontaneous immune responses. In recent years, STING has emerged as an important target that activates antitumor immune pathways for cancer immunotherapy. Studies have observed punctate structures upon the addition of cGAMP to STING, indicating that oligomerization or even higher order architecture may be critical for activation. Therapeutic attempts to deliver cGAMP into the cytosol of target cells, where STING is located, have been limited by its inherent properties as a small, dual negatively charged molecule. Moreover, the rapid enzymatic degradation and clearance as well as off-target toxicity of cGAMP have hindered its further clinical application. Therefore, the pharmaceutical industry has devoted great efforts to the chemical modification of natural cyclic dinucleotides (CDNs) as well as novel STING agonists to improve their bioavailability and pharmacological activity.

[0003] pH sensitive polymers with linear or cyclic tertiary amine structures, have shown strong vaccine adjuvant effect through the STING-dependent pathway. Moreover, some pH sensitive polymers, (e.g.7-membered cyclic amine, PC7A) can function as polyvalent STINGAttorney Docket No.100007_00059 agonists. These pH sensitive polymers can act through polymer-induced phase separation of STING for innate immune activation with more prolonged cytokine expressions than cGAMP. Moreover, a combination of polyvalent STING activation by a pH sensitive polymer, (e.g. PC7A) with cytosol delivered or cell-intrinsic cGAMP stimulation further offers a synergistic and robust strategy to mount antitumor immunity for cancer immunotherapy. SUMMARY OF THE INVENTION

[0004] In some aspects, the present disclosure provides methods of treating cancer comprising administering to a patient in need thereof (i) a sting activating micelle composition comprising: (a) a sting activating polymer of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: O OXOry1, wherein:n1is an x1is an integer from 20-300; y1is an integer from 0-10; X is a halogen, -OH, or -C(O)OH; R1and R2are each independently hydrogen or optionally substituted C1-C6alkyl; R3and R4are each independently an optionally substituted C1-C6alkyl, C3-C10cycloalkyl or aryl; or R3and R4are taken together with the corresponding nitrogen to which they are attached form an optionally substituted 5 to 7-membered ring; R5is hydrogen or -C(O)CH3, and (b) a cyclic dinucleotide STING agonist (e.g., cGAMP), and (ii) an anti-PD1 composition comprising an isolated human monoclonal antibody or antigen- binding fragment thereof that binds specifically to human programmed death-I (PD-1) protein (e.g., cemiplimab).

[0006] In some embodiments, the of the block copolymer of Formula (I), R1and R2are each independently an optionally substituted C1-C6alkyl. In some embodiments, R1and R2are each independently -CH3. In some embodiments, R3and R4are each independently an optionally substituted C1-C6 alkyl. In some embodiments, R3and R4are each independently -CH2CH3, - CH2CH2CH3, or -CH2CH2CH2CH3. In some embodiments, R3and R4are taken together with the corresponding nitrogen to which they are attached form an optionally substituted 5 to 7-Attorney Docket No.100007_00059 membered ring. In some embodiments, R3and R4taken together are -CH2(CH2)2CH2-, - CH2(CH2)3CH2-, or -CH2(CH2)4CH2-. In some embodiments, R5is hydrogen. In some embodiments, R5is -C(O)CH3. In some embodiments, the non-peptide STING agonist is a cyclic dinucleotide. In some embodiments, the cyclic dinucleotide is cGAMP.

[0007] In another aspect of the invention is a method for treating cancer in a subject in need thereof, comprising administration to the subject a pharmaceutically effective amount of the combination therapy as noted above. In some embodiments, the cancer comprises a solid tumor.

[0008] In some embodiments, the tumor is of a cancer, wherein the cancer is of the breast, ovarian, prostate, peritoneal metastasis, colorectal, bladder, esophageal, head and neck (HNSCC), lung, brain, kidney, or skin (including melanoma and sarcoma).

[0009] Other objects, features and advantages of the block copolymers, micelle compositions, and methods described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings below. The patent application file contains at least one drawing executed in color. Copies of this patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG.1 (Prior Art) shows that cGAMP-PC7A nanoparticle synergizes with anti-PD1 in immunotherapy of tumor-bearing animals. FIG.2 shows that a a sting activating copolymer shows anti-tumor efficacy as monotherapy and in combination with anti-PD1 antibody in multiple syngeneic tumor models. FIG.3 shows the trial design according to an embodiment of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] Provided herein are methods of treating cancer comprising administering to a patient in need thereofAttorney Docket No.100007_00059 (i) a sting activating micelle composition comprising: (a) a sting activating block copolymer of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: O OXOry1x1 , wherein: n1is an integerx1is an integer from 20-300; y1is an integer from 0-10; X is a halogen, -OH, or -C(O)OH; R1and R2are each independently hydrogen or optionally substituted C1-C6alkyl; R3and R4are each independently an optionally substituted C1-C6alkyl, C3-C10cycloalkyl or aryl; or R3and R4are taken together with the corresponding nitrogen to which they are attached form an optionally substituted 5 to 7-membered ring; R5is hydrogen or -C(O)CH3, and (b) a cyclic dinucleotide STING agonist (e.g., cGAMP), and (ii) an anti-PD1 composition comprising an isolated human monoclonal antibody or antigen- binding fragment thereof that binds specifically to human programmed death-I (PD-1) protein (e.g., cemiplimab). The sting activating micelle compositions used in connection with he anti-PD1 composiitons disclosed herein are described in U.S. Patent No.12,036,319, entitled "Polyvalent Sting Activating Compositions and Uses Thereof," filed September 8, 2021, which is incorporated herein by reference. (i)(a) Block copolymersthe sting activating block copolymer composition comprises a block copolymer of Formula (I), or a pharmaceutically acceptable, salt, solvate, or hydrate thereof.

[0014] In some embodiments of Formula (I), R1and R2are each independently an optionally substituted C1-C6alkyl. In some embodiments, R1and R2are each independently -CH3, -CH2CH3, -CH2CH2CH3, or -CH2CH2CH2CH3. In some embodiments, R1and R2are each independently - CH3. In some embodiments, R1and R2are each independently hydrogen.

[0015] In some embodiments of Formula (I), the R3and R4are each independently an optionally substituted C1-C6alkyl. In some embodiments, the alkyl is a straight chain or a branch alkyl. In some embodiments, the alkyl is a straight chain alkyl. In some embodiments, R3and R4Attorney Docket No.100007_00059 are each independently -CH2CH3, -CH2CH2CH3, or -CH2CH2CH2CH3. In some embodiments, R3and R4are each independently -CH2CH2CH2CH3.

[0016] In some embodiments, the alkyl is a branched alkyl. In some embodiments, R3and R4are each independently -CH(CH3)2or -CH(CH3)CH2CH3. In some embodiments, R3and R4are each independently -CH(CH3)2.

[0017] In some embodiments of the block copolymer of Formula (I), R3and R4are each independently an optionally substituted C3-C10cycloalkyl or aryl. In some embodiments, R3and R4are each independently an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R3and R4are each independently an optionally substituted phenyl.

[0018] In some embodiments of the block copolymer of Formula (I), R3and R4are taken together with the corresponding nitrogen to which they are attached form an optionally substituted 5 to 7-membered ring. In some embodiments, R3and R4taken together are -CH2(CH2)2CH2-, - CH2(CH2)3CH2-, or -CH2(CH2)4CH2-. In some embodiments, R3and R4taken together are - CH2(CH2)2CH2-. In some embodiments, R3and R4taken together are -CH2(CH2)3CH2-. In some embodiments, R3and R4taken together are -CH2(CH2)4CH2-.

[0019] In some embodiments of the block copolymer of Formula (I), R5is hydrogen. In some embodiments, R5is -C(O)CH3. In some embodiments, R5is acetyl.

[0020] In some embodiments of the block copolymer of Formula (I), y1, is an integer 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or any range derivable therein. In some embodiments, y1, is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, y1, is 1, 2, or 3. In some embodiments, y1, is 0.

[0021] In some embodiments, the block copolymer of Formula (I) has the structure of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: O OX.

[0022] In somecopolymer. In some embodiments, the block copolymer comprises a hydrophilic polymer segment and a hydrophobic segment.

[0023] In some embodiments, the hydrophilic polymer segment comprises poly(ethylene oxide) (PEO). In some embodiments, the hydrophilic polymer segment is about 2 kD to about 10 kD in size. In some embodiments, the hydrophilic polymer segment is about 2 kD to about 5 kD in size. In some embodiments, the hydrophilic polymer segment is about 3 kD to about 8 kD in size. InAttorney Docket No.100007_00059 some embodiments, the hydrophilic polymer segment is about 4 kD to about 6 kD in size. In some embodiments, the hydrophilic polymer segment is about 5 kD in size.

[0024] In some embodiments, n1is an integer from 1-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30- 35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, 95-99, 100-109, 110-119, 120-129, 130-139, 140-149, 150-159, 160-169, 170-179, 180-189, 190-199 or any range derivable therein. In some embodiments, n1is an integer from 60-150, 100-140, or 110- 120. In some embodiments, n1is 100-140.

[0025] In some embodiments, the block copolymer comprises a hydrophobic polymer segment. In some embodiments, the hydrophobic polymer segment is selected from: X , , wherein x isIn some segment a In some embodiments, the hydrophobic segment comprises a cyclic amine. In some embodiments, the cyclic amine is a 5 to 8-membered cyclic amine. In some embodiments, the cyclic amine is a 7- anyAttorney Docket No.100007_00059 range derivable therein. In some embodiments, x1is an integer from 50-200, 60-160, or 90-140. In some embodiments, x1is 90-140.

[0028] In some embodiments, X is a terminal group . In some embodiments, the terminal capping group is the product of an atom transfer radical polymerization (ATRP) reaction. For example, the terminal capping group may be a halogen, such as -Br, when atom transfer radical polymerization (ATRP) is used. In some embodiments, X is Br. In some embodiments, X is independently –OH. In some embodiments, each X is an acid. In some embodiments, X is – C(O)OH. In some embodiments, X is H. The end group may optionally be further modified following polymerization with an appropriate moiety. (i)(b) Non-Peptide STING agonists the non-peptide STING agonist is a small molecule. Insome non- STING agonist is a dinucleotide. In some embodiments, the non-peptide STING agonist is a synthetic cyclic dinucleotide (CDN). In some embodiments, the CDN is naturally occurring or synthetic CDN. The CDN can be modified as the 2’ hydroxyl or at the 4’ hydroxyl site. In some instances, the CDN the 2’ hydroxyl group in a locked or bridged ribose modification (e.g., locked nucleic acid or LNA) in which the oxygen molecule bound at the 2’ carbon is linked to the 4’ carbon by a methylene group, thus forming a 2′-C,4′-C-oxy- methylene-linked bicyclic ribonucleotide monomer.

[0030] In some embodiments, the cyclic dinucleotide has the structure of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: O O P O A1P O , wherein:A1and A2are each independently OH or SH; B1and B2are each independently guanine or adenine; and R10is H, halogen, OH, OCH3; and R11is halogen or OH.

[0031] In some embodiments of Formula (IIa) or (IIb), or a pharmaceutically acceptable salt, solvate or hydrate thereof, R10is OH or OCH3. In some embodiments, R10is fluoro or chloro. In some embodiments, R11is OH. In some embodiments, R11is fluoro or chloro. In some embodiments, A1and A2are each independently OH. In some embodiments, A1and A2are each independently SH. In some embodiments, B1and B2are each independently guanine. In someAttorney Docket No.100007_00059 embodiments, B1and B2are each independently adenine. In some embodiments, one of B1or B2is guanine and the other is adenine.

[0032] In some embodiments, the cyclic dinucleotide of Formula (IIa) has the structure of Formula (IIa)(1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 1). structure of Formula (III),NH2N , wherein:A1are OH or SH; Y1and Y2are each independently -CH- or -O-.

[0034] In some embodiments of Formula (III), or a pharmaceutically acceptable salt, solvate or hydrate thereof, A1and A2are each independently OH. In some embodiments, A1and A2are each independently SH. In some embodiments, Y1and Y2are each independently -O-. In some embodiments, Y1and Y2are each independently -CH-. In some embodiments, one of Y1or Y2is -O- while the other is -CH-.

[0035] Naturally occurring cyclic dinucleotides include CDG, CDA, 3’,3’-cGAMP and 2’,3’-cGAMP. In some embodiments, the cyclic dinucleotide is cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP or cGAMP), or a pharmaceutically acceptable salt, solvate, or hydrate. cGAMP functions as an endogenous second messenger inducing STING-dependent type I interferon response. cGAMP has also been shown to be an effective adjuvant that boosts the production of antigen-specific antibodies and T cell responses in mice. In some embodiments, cGAMP is 2’,3’-cGAMP. In some embodiments,Attorney Docket No.100007_00059 cGAMP has the following structure, or a pharmaceutically acceptable salt, solvate, of hydrate thereof: O O N NH 2 .

[0036] In some selected from:N N or X3and Y3are each independently OH,or hydrate thereof.

[0037] In some embodiments the cyclic dinucleotide is a compound selected from:Attorney Docket No.100007_00059(Attorney Docket No.100007_00059 NH2N N , ,Attorney Docket No.100007_00059 NH2N N ,Attorney Docket No.100007_00059 a pharmaceuticallymodified. In some embodiments, the cyclic dinucleotide is an S-alkylated dinucleotide. In some embodiments, the cyclic dinucleotide is the compound selected from: OC10H21Attorney Docket No.100007_00059 NH2O N N aor

[0041] In some embodiments, the cyclic dinucleotide is modified with a T cell epitome KLFAVWKITYKDT derived from polio virus in combination with a glycopeptide antigen. In some embodiments, the cyclic dinucleotide is:Attorney Docket No.100007_00059 adinucleotide. In some embodiments, the non-peptide STING agonist is a small molecule such as flavone acetic acid (FAA), 10-carboxymethyl-9-acridanone (CMA), or α-Mangostin. In some embodiments, the non-peptide STING agonist is a compound selected from: O O orsuch as a benzothiophene. In some embodiments, the small molecule STING agonist is a compound selected from: a pharmaceutically

[0044] In some embodiments, the non-peptide STING agonist is a compound selected from:Attorney Docket No.100007_00059 Br O ,In some non- STING .the non-peptide STING agonist is ADU-S100, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, ADU-100 has the structure:Attorney Docket No.100007_00059 . STING agonist is an amidobenzimidazole.some non- has the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: O H2N O ,W is H or -OCH3; and V is H or -O-(C1-C3)alkyl-(C3-C6)heterocycle.

[0048] In some embodiments of Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, C-D is a C2-C8alkylene. In some embodiments, C-D is a C2-C8alkenylene. In some embodiments, C-D is -CH2CH2- or -CH=CH-. In some embodiments, W is hydrogen. In some embodiments, W is -OCH3. In some embodiments, V is hydrogen. In some embodiments, V is -O-(CH2)3-C6 heterocycloalklyl.

[0049] In some embodiments, the non-peptide STING agonist is selected from:Attorney Docket No.100007_00059 O N aO S P

[0051] In some embodiments, the non-peptide STING agonist is encapsulated within a micelle comprising the block copolymer. In some embodiments, the micelle comprises one or more different types of block copolymer components from various unimers. In some embodiments, the non-peptide STING agonist is non-covalently encapsulated by the micelle comprising the block copolymer.

[0052] In some embodiments, the pharmaceutical compositing comprises one or more micelles wherein each micelle comprises (i) a sting activating block copolymer of Formula (I) and (ii) a non-peptide STING agonist. In some embodiments, the one of more micelles comprise two, three, or more different non-peptide STING agonists. In some embodiments, the one or moreAttorney Docket No.100007_00059 micelles comprise two or three different non-peptide STING agonists. In some embodiments, the one of more micelles comprise the same non-peptide STING agonist.

[0053] The use of micelles in cancer therapy may enhance anti-tumor efficacy and reduce toxicity to healthy tissues, in part due to the size of the micelles. While small molecules such as certain chemotherapeutic agents can enter both normal and tumor tissues, non-targeted micelle nanoparticles may preferentially cross leaky tumor vasculature. The size of the micelles will typically be in the nanometer scale (i.e., between about 1 nm and 1 μm in diameter). In some embodiments, the micelle has a diameter of less than about 1 μm. In some embodiments, the micelle has a size of about 10 to about 200 nm. In some embodiments, the micelle has a size of about 20 to about 100 nm. In some embodiments, the micelle has a size of about 30 to about 50 nm.

[0054] In some embodiments, the non-peptide STING agonist is not encapsulated within the micelle. In some embodiments, the pharmaceutical composition comprises a mixture of components comprising (i) a block copolymer of Formula (I) and (ii) a non-peptide STING agonist. In some embodiments, the mixture comprises two, three, or more different non-peptide STING agonists. In some embodiments, the mixture comprises two or three different non-peptide STING agonists. In some embodiments, the mixture comprises one distinct type of non-peptide STING agonist. In some embodiments, the mixture comprises one or more different types of block copolymer components from various unimers.

[0055] In some embodiments, the pharmaceutical composition comprises a 10:1, 5:3, 5:2, 5:1, 4:1, 3:2, 3:1, 2:1; 1:1, or any combination therein, molar ratio of (i) a block copolymer of Formula (I) and (ii) a non-peptide STING agonist. In some embodiments, the pharmaceutical composition comprises a 2:1 or 1:1 molar ratio. In some embodiments, the non-peptide STING agonist is a small molecule. In some embodiments, the non-peptide STING agonist is a cyclic dinucleotide. In some embodiments, the non-peptide STING agonist is cGAMP.

[0056] In some embodiments, the pharmaceutical composition further comprises a saline or a saccharide solution. In some embodiments, the saccharide or saline solution is a buffer. In some embodiments, the saccharide solution is a glucose solution. In some embodiments, the saline solution is a sodium chloride solution.

[0057] In some embodiments, the pharmaceutical composition is a pH responsive composition. The pH responsive compositions disclosed herein, comprise one or more pH- responsive micelles and / or nanoparticles that comprise block copolymers and a non-peptide STING agonist. Each block copolymer comprises a hydrophilic polymer segment and a hydrophobic polymer segment wherein the hydrophobic polymer segment comprises an ionizable amine group to render pH sensitivity. This pH sensitivity is exploited to provide compositions suitable as drug delivery therapeutics.Attorney Docket No.100007_00059

[0058] The micelles may have different pH transition values within physiological range, in order to target specific cells or microenvironments. In some embodiments, the micelle has a pH transition value of about 5 to about 8. In some embodiments, the micelle has a pH transition value of about 5 to about 6. In some embodiments, the micelle has a pH transition value of about 6 to about 7. In some embodiments, the micelle has a pH transition value of about 7 to about 8. In some embodiments, the micelle has a pH transition value of about 6.3 to about 6.9. In some embodiments, the micelle has a pH transition value of about 5.0 to about 6.2. In some embodiments, the micelle has a pH transition value of about 5.9 to about 6.2. In some embodiments, the micelle has a pH transition value of about 5.0 to about 5.5. In some embodiments, the pH transition point is 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5.

[0059] The pH-sensitive micelle compositions of the invention may advantageously have a narrow pH transition range, in contrast to other pH sensitive compositions in which the pH response is very broad (i.e.2 pH units). This pH transition is the transition point at which the micelle dissociates, releasing the payload or activating the photophore (i.e., an indocyanine green dye). In some embodiments, the micelles have a pH transition range of less than about 1 pH unit. In various embodiments, the micelles have a pH transition range of less than about 0.9, less than about 0.8, less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, less than about 0.1 pH unit. In some embodiments, the micelles have a pH transition range of less than about 0.5 pH unit. In some embodiments, the micelles have a pH transition range of less than about 0.25 pH unit. The narrow pH transition range advantageously provides a sharper pH response that can result in complete release the therapeutic payload, such as the non-peptide STING agonist, with subtle changes of pH. (ii) anti-PD1 composition

[0060] The anti-PD1 compositions used herein are described in U.S. Patent No. 9,987,500, entitled "Human antibodies to PD-1," which was filed January 23, 2015, which is incorporated by reference herein in its entirety. Any of the anti-PD1 compositions described in U.S. Patent No.9,987,500 may be used herein.

[0061] The term “PD-1” refers to the programmed death-1 protein, a T-cell co-inhibitor, also known as CD279. The amino acid sequence of full-length PD-1 is provided in GenBank as accession number NP_005009.2. The immunogen was administered directly, with an adjuvant to stimulate the immune response, to a VELOCIMMUNE® mouse comprising DNA encoding human Immunoglobulin heavy and kappa light chain variable regions. The antibody immune response was monitored by a PD-1-specific immunoassay. When a desired immune response was achieved splenocytes were harvested and fused with mouse myeloma cells to preserve their viability and form hybridoma cell lines. The hybridoma cell lines were screened and selected to identify cell lines that produce PD-1-specific antibodies. Using this technique, and theAttorney Docket No.100007_00059 immunogen described above, several anti-PD-1 chimeric antibodies (i.e., antibodies possessing human variable domains and mouse constant domains) were obtained. Other methods for obtaining anti-PD1 antibodies are described in U.S. Patent No.9,987,500, including isolated directly from antigen-positive B cells without fusion to myeloma cells, as described in U.S. 2007 / 0280945A1, which is incorporated by reference in its entirety.

[0062] The anti-PD1 composition may include antibodies, or antigen-binding fragments thereof, comprising a HC and a LC amino acid sequence pair (HC / LC) The HC / LC amino acid sequence pair may be selected from SEQ ID NOs: 9 / 10 (which are 330 / 331 in U.S. Patent No. 9,987,500.) Other sequences provided in Table 3 of U.S. Patent No.9,987,500. Each heavy chain sequence comprised a variable region (VH or HCVR; comprising HCDR1, HCDR2 and HCDR3) and a constant region (comprising C H1, CH2 and CH3 domains). Each light chain sequence comprised a variable region (VL or LCVR; comprising LCDR1, LCDR2 and LCDR3) and a constant region (CO. SEQ ID NO: 9 comprised a HCVR comprising amino acids 1-117 and a constant region comprising amino acids 118-444. SEQ ID NO: 10 comprised a LCVR comprising amino acids 1-107 and a constant region comprising amino acids 108-214.

[0063] The present invention provides antibodies, or antigen-binding fragments thereof, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR / LCVR amino acid sequence pair. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of the structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within an antibody.

[0064] The following table sets forth the amino acid sequence identifiers of the heavy and light chain variable regions and CDRs of selected anti-PD-1 antibodies of an embodiment of the invention. The corresponding nucleic acid sequences may be found in U.S. Patent No. 9,987,500, and are incorporated herein by reference. SEQ ID NOs: Antibody HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H2M7798N 1 3 4 5 2 6 7 8Attorney Docket No.100007_00059

[0065] The anti-PD1 composition may be provided as a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution with a pH of 6. The solution may contain trace amounts of translucent to white particles. Each vial may contains 350 mg of the anti-PD1 compsotion. Each mL contains anti-PD1 composition 50 mg, L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.1 mg), sucrose (50 mg), L-proline (15 mg), polysorbate 80 (2 mg), and Water for Injection, USP. In one aspect, the anti-PD1 composition is cemiplimab-rwlc. Combination Therapy with Cemplipimab

[0066] The methods described herein involve administering in roughly the same time period both the sting activating polymer and non-pepetide sting agonist on the one hand (ONM- 501), and an anti-PD1 composition (Cemiplimab) on the other hand. ONM-501 is a micellar formulation consisting of a unique STING-activating synthetic polymeric micelle loaded with the endogenous STING agonist cGAMP. The micelles are formed using a pH-responsive di-block copolymer and perform four major actions: 1) the PC7A nanoparticle shell shields cGAMP from degradation and increases tumor retention, 2) endocytosis of nanoparticles and pH-activated micelle dissociation and payload release in endolysosomes enhances intracellular delivery of cGAMP 3) the combination of cGAMP canonical binding, and PC7A polymer noncanonical binding on STING protein yields synergistic STING activation 4) stabilization of the STING poly-condensate by PC7A polymers delays STING degradation and prolongs STING activation. These factors combine to help generate a stronger and more prolonged innate immune response that more effectively translates to a robust adaptive immune response Methods of Use

[0067] Aerobic glycolysis, known as the Warburg effect, in which cancer cells preferentially uptake glucose and convert it into lactic acid or other acids, occurs in all solid cancers. Lactic acid or other acids preferentially accumulates in the extracellular space due to monocarboxylate transporters or other transporters. The resulting acidification of the extra- cellular space promotes remodeling of the extracellular matrix for further tumor invasion and metastasis.

[0068] Some embodiments provided herein describe compounds that form micelles at physiologic pH (7.35-7.45). In some embodiments, the compounds described herein are non- covalently conjugated to a therapeutic agent. In some embodiments, the micelle has a molecular weight of greater than 2×107Daltons. In some embodiments, the micelle has a molecular weight of ~2.7×107Daltons. In some embodiments, the therapeutic agents are sequestered within the micelle core at physiologic pH (7.35-7.45) (e.g., during blood circulation). In some embodiments, when the micelle encounters an acidic environment (e.g., tumor tissues), the micelles dissociate into individual compounds with an average molecular weight of about 3.7×104Daltons, allowingAttorney Docket No.100007_00059 the release of the therapeutic agent. In some embodiments, the micelle dissociates at a pH below the pH transition point (e.g. the acidic state of tumor microenvironment).

[0069] In some embodiments, the therapeutic agent may be incorporated into the interior of the micelles. Specific pH conditions (e.g. acidic pH present in tumors and endocytic compartments) may lead to rapid protonation and dissociation of micelles into unimers, thereby releasing the therapeutic agent (e.g. a drug). In some embodiments, the micelle provides stable drug encapsulation at physiological pH (pH 7.4), but can quickly release the drug in acidic environments.

[0070] In some instances, the pH-sensitive micelle compositions described herein have a narrow pH transition range. In some embodiments, the micelles described herein have a pH transition range (ΔpH10-90%) of less than 1 pH unit. In various embodiments, the micelles have a pH transition range of less than about 0.9, less than about 0.8, less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, less than about 0.1 pH unit. In some embodiments, the micelles have a pH transition range of less than about 0.5 pH unit. In some embodiments, the pH transition range is less than 0.25 pH units. In some embodiments, the pH transition range is less than 0.15 pH units. A sharp transition point allows the micelles to dissociate with the acidic tumor microenvironment.

[0071] These micelles may be used as drug-delivery agents and STING agonists. Micelles comprising a drug may be used to treat cancers, or other diseases wherein the drug may be delivered to the appropriate location due to localized pH differences (e.g. a pH different from physiological pH (7.4). In some embodiments, the disorder treated is a cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the tumor is a secondary tumor from metastasis of a primary tumor(s). In some embodiments, the drug-delivery may be to a lymph node or to a peritoneal or pleural surface.

[0072] In some embodiments is a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compositions disclosed herein.

[0073] In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0074] In some embodiments, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, gastrointestinal tract, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma (HNSCC), lung cancer, ovarian cancer, prostate cancer, bladder cancer, urethral cancer, esophageal cancer, colorectal cancer, peritoneal metastasis, renal cancer, or brain, skin (includingAttorney Docket No.100007_00059 melanoma and sarcoma). In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma (HNSCC), esophageal cancer, colorectal cancer, or renal cancer.

[0075] In some embodiments, the cancer is a solid tumor.

[0076] In some embodiments, the tumor is reduced by about 5%, about 10%, about 15%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the tumor is reduced by about 50%. In some embodiments, the tumor is reduced by about 60%. In some embodiments, the tumor is reduced by about 70%. In some embodiments, the tumor is reduced by about 75%. In some embodiments, the tumor is reduced by about 80%. In some embodiments, the tumor is reduced by about 85%. In some embodiments, the tumor is reduced by about 90%. In some embodiments, the tumor is reduced by about 95%. In some embodiments, the tumor is reduced by about 99%.

[0077] The stimulator of interferon genes (STING) has received extensive interest as a target for autoimmunity and cancer immunotherapy. Early phase clinical trials using small molecule agonists, however, show limited antitumor efficacy and have dose-limiting toxicity.

[0078] In another aspect is a method of activating the STING pathway in a patient comprising administering to the patient in need thereof a pharmaceutical composition described herein.

[0079] In some embodiments is a method of activating the STING pathway in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described here.

[0080] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0081] In some embodiments, the method comprises administering the composition once. In some embodiments, the method comprises administering the composition two or more times. In some embodiments, the method comprises administering the composition before cancer surgery. Kits

[0082] The present disclosure also provides kits. Any of the components disclosed herein may be combined in a kit. In certain embodiments the kits comprise a composition of the preceding embodiments described herein.

[0083] The kits will generally include at least one vial, test tube, flask, bottle, syringe or other container, into which a component may be placed, and preferably, suitably aliquoted. Where there is more than one component in the kit, the kit also will generally contain a second, third or other additional containers into which the additional components may be separately placed. However, various combinations of components may be comprised in a container. In some embodiments, all of the micelle populations in a series are combined in a single container.Attorney Docket No.100007_00059 In other embodiments, some or all of the micelle population in a series are provided in separate containers.

[0084] The kits of the present disclosure also will typically include packaging for containing the various containers in close confinement for commercial sale. Such packaging may include cardboard or injection or blow molded plastic packaging into which the desired containers are retained. A kit may also include instructions for employing the kit components. Instructions may include variations that can be implemented. Definitions

[0085] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0086] 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. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0087] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0088] “Oxo” refers to the =O substituent.

[0089] “Thioxo” refers to the =S substituent.

[0090] “Alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10alkyl, C1-C9alkyl, C1-C8alkyl, C1-C7alkyl, C1-C6alkyl, C1- C5alkyl, C1-C4alkyl, C1-C3alkyl, C1-C2alkyl, C2-C8alkyl, C3-C8alkyl and C4-C8alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl, ethyl, s- butyl, or 1-ethyl-propyl. Unless stated otherwise specifically in the specification, an alkyl groupAttorney Docket No.100007_00059 may be optionally substituted as described below. “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0091] “Alkoxy” refers to a radical of the formula -OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0092] “Heteroalkylene” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to -OCH2OMe, -OCH2CH2OMe, or - OCH2CH2OCH2CH2NH2. Representative heteroalkylene groups include, but are not limited to - OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0093] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0094] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0095] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.

[0096] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to theAttorney Docket No.100007_00059 carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to: O O N N O S OH C N N NO NN,N, NH,N,N,aromatic radical, whereinCycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a 3- to 6-membered cycloalkyl. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 3,4-dihydronaphthalen-1(2H)-one. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0098] “Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

[0099] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

[0100] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0101] “Haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy,Attorney Docket No.100007_00059 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0102] “Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” refers to a stable 3- to 14-membered non-aromatic ring radical comprising 2 to 13 carbon atoms and from one to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a C2-C7heterocycloalkyl. In some embodiments, the heterocycloalkyl is a C2-C6heterocycloalkyl. In some embodiments, the heterocycloalkyl is a C2- C5heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 5-membered heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0103] “Heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl is monocyclic or bicyclic. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl,Attorney Docket No.100007_00059 pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.

[0104] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1- C6alkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2alkyl, nitro, and amino, including mono- and di-substituted amino groups (e.g., -NH2, -NHR, -N(R)2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, - CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, optional substituents are independently selected from fluoro, chloro, -CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) includes oxo (=O).

[0105] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:Attorney Docket No.100007_00059 OH O O OH N N HH HHtreatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0107] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[0108] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0109] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the block copolymer, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0110] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble andAttorney Docket No.100007_00059 more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt- forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0111] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a block copolymer with an acid. In some embodiments, the block copolymer of Formula (I) (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0112] In some embodiments, a block copolymer of Formula (I) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0113] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a block copolymer of Formula (I) with a base. In some embodiments, the block copolymer of Formula (I) is acidic and is reacted with a base. In such situations, an acidic proton of the block copolymer of Formula (I) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, block copolymers described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, block copolymers described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with block copolymers that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate,Attorney Docket No.100007_00059 potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the block copolymers provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, melamine salt, N-methylglucamine salt or ammonium salt.

[0114] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0115] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of block copolymers having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity.

[0116] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0117] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl,123I,124I,125I,131I,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0118] As used herein, “pH responsive system,” “pH responsive composition,” “micelle,” “pH-responsive micelle,” “pH-sensitive micelle,” “pH-activatable micelle” and “pH- activatable micellar (pHAM) nanoparticle” are used interchangeably herein to indicate a micelle comprising one or more compounds, which disassociates depending on the pH (e.g., above or below a certain pH). As a non-limiting example, at a certain pH, the block copolymers of Formula (I) is substantially in micellar form. As the pH changes (e.g., decreases), the micelles begin to disassociate, and as the pH further changes (e.g., further decreases), the block copolymers of Formula (I) is present substantially in disassociated (non-micellar) form.Attorney Docket No.100007_00059

[0119] As used herein, “pH transition range” indicates the pH range over which the micelles disassociate.

[0120] As used herein, “pH transition value” (pH) indicates the pH at which half of the micelles are disassociated.

[0121] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intratumoral, or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. In some embodiments, the compositions described herein are administered intravenously.

[0122] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0123] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0124] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0125] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.Attorney Docket No.100007_00059

[0126] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0127] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. Following longstanding patent law, the words “a” and “an,” when used in conjunction with the word “comprising” in the claims or specification, denotes one or more, unless specifically noted.

[0128] The term “PD-1” refers to the programmed death-1 protein, a T-cell co-inhibitor, also known as CD279. The amino acid sequence of full-length PD-1 is provided in GenBank as accession number NP_005009.2 and is also referred to herein as SEQ ID NO: 327. The term “PD- 1” also includes protein variants of PD-1 having the amino acid sequence of SEQ ID NOs: 321, 322, 323, or 324. The term “PD-1” includes recombinant PD-1 or a fragment thereof. The term also encompasses PD-1 or a fragment thereof coupled to, for example, histidine tag, mouse or human Fc, or a signal sequence such as ROR1. For example, the term includes sequences exemplified by SEQ ID NOs: 323 or 324, comprising a mouse Fc (mlgG2a) or human Fc (hIgG1) at the C-terminal, coupled to amino acid residues 25-170 of full-length PD-1 with a C93S change. Protein variants as exemplified by SEQ ID NO: 321 comprise a histidine tag at the C-terminal, coupled to amino acid residues 25-170 of full length PD-1. Unless specified as being from a non- human species, the term “PD-1” means human PD-1.

[0129] PD-1 is a member of the CD28 / CTLA-4 / ICOS family of T-cell co-inhibitors. PD- 1 is a 288-amino acid protein with an extracellular N-terminal domain which is IgV-like, a transmembrane domain and an intracellular domain containing an immunoreceptor tyrosine-based inhibitory (ITIM) motif and an immunoreceptor tyrosine-based switch (ITSM) motif (Chattopadhyay et al 2009, Immunol. Rev.). The PD-1 receptor has two ligands, PD-ligand-1 (PD-L1) and PD-L2. The term “PD-L1” refers to the ligand of the PD-1 receptor also known as CD274 and B7H1. The amino acid sequence of full-length PD-L1 is provided in GenBank as accession number NP_054862.1 and is also referred to herein as SEQ ID NO: 328. The term also encompasses PD- L1 or a fragment thereof coupled to, for example, histidine tag, mouse or human Fc, or a signal sequence such as ROR1. For example, the term includes sequences exemplified by SEQ ID NOs: 325 or 326, comprising a mouse Fc (mlgG2a) or human Fc (hIgG1) at the C-terminal, coupled toAttorney Docket No.100007_00059 amino acid residues 19-239 of full-length PD-L1. PD-L1 is a 290 amino acid protein with an extracellular IgV-like domain, a transmembrane domain and a highly conserved intracellular domain of approximately 30 amino acids. PD-L1 is constitutively expressed on many cells such as antigen presenting cells (e.g., dendritic cells, macrophages, and B-cells) and on hematopoietic and non-hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and sites of immune privilege). PD-L1 is also expressed on a wide variety of tumors, virally-infected cells and autoimmune tissue, and is a component of the immunosuppressive milieu (Ribas 2012, NEJM 366: 2517-2519).

[0130] As used herein, the term “T-cell co-inhibitor” refers to a ligand and / or receptor which modulates the immune response via T-cell activation or suppression. The term “T-cell co- inhibitor”, also known as T-cell co-signaling molecule, includes, but is not limited to, lymphocyte activation gene 3 protein (LAG-3, also known as CD223), cytotoxic T-lymphocyte antigen-4 (CTLA-4), B and T lymphocyte attenuator (BTLA), CD-28, 2B4, LY108, T-cell immunoglobulin and mucin 3(TIM3), T-cell immunoreceptor with immunoglobulin and ITIM (TIGIT; also known as VSIG9), leucocyte associated immunoglobulin-like receptor 1 (LAIR1; also known as CD305), inducible T-cell costimulator (ICOS; also known as CD278), V-domain Ig suppressor of T-cell activation (VISTA) and CD160.

[0131] As used herein, the term “Fc receptor” refers to the surface receptor protein found on immune cells including B lymphocytes, natural killer cells, macrophages, basophils, neutrophils, and mast cells, which has a binding specificity for the Fc region of an antibody. The term “Fc receptor” includes, but is not limited to, a Fcγ receptor [e.g., FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a), and FcγRIIIB (CD16b)], Fcα receptor (e.g., FcαRI or CD89) and Fcε receptor [e.g., FcεRI, and FcεRII (CD23)].

[0132] The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds (i.e., “full antibody molecules”), as well as multimers thereof (e.g. IgM) or antigen-binding fragments thereof. Each heavy chain is comprised of a heavy chain variable region (“HCVR” or “VH”) and a heavy chain constant region (comprised of domains C H1, CH2 and CH3). Each light chain is comprised of a light chain variable region (“LCVR or “VL”) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments of the invention, the FRs of the antibody (or antigen binding fragment thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.Attorney Docket No.100007_00059 EXAMPLES

[0133] Block copolymers and micelles described herein are synthesized using standard synthetic techniques or using methods known in the art.

[0134] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. Block copolymers are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Some abbreviations used herein are as follows: DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: dimethyl formamide DMF-DMA: N,N-dimethylformamide dimethyl acetal EDCI: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide EtOAc: ethyl acetate EtOH: ethanol MeOH: methanol PMDETA: N,N,N′,N′′,N′′-Pentamethyldiethylenetriamine CDI carbonyldiimidazole TEA: triethyl amine Hr Hour(s) ISR Incurred sample reanalysis IV Intravenous kg Kilogram mg Milligram(s) mL Milliliters(s) µg Microgram(s) µm Mircons(s) NC Not calculated NR Not reported

[0135] Suitable PEG polymers may be purchased (for example, from Sigma Aldrich ) or may be synthesized according to methods known in the art. In some embodiments, the hydrophilic polymer can be used as an initiator for polymerization of the hydrophobic monomers to form a block copolymer. For example, 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers (e.g. narrowly distributed MPC polymers) can be prepared by atom transfer radical polymerization (ATRP) with commercially available small molecule initiators such as ethyl 2-bromo-2-Attorney Docket No.100007_00059 methylpropanoate (e.g. from Sigma Aldrich). These resulting MPC polymers can be used as macromolecular ATRP initiators to further copolymerize with other monomers to form block polymers can be synthesized using atom transfer radical polymerization (ATRP) or reversible addition- fragmentation chain transfer (RAFT) methods.

[0136] Previous studies have shown an association between elevated type I IFN production and increased tumor infiltration of PD-1+cytotoxic T lymphocytes. STING activation by cGAMP-loaded PC7A NP may synergize with PD-1 blockade. FIG.1 (Prior Art) shows that cGAMP-PC7A nanoparticle synergizes with anti-PD1 in immunotherapy of tumor-bearing animals. (a-c) TC1 and (d-f) MC38 tumor-bearing mice were injected intratumorally with 5% glucose (mock) or cGAMP-loaded PC7A NP, and injected intraperitoneally with saline or anti- PD1 (200 μg) at indicated time points. Mean tumor volume (a, d), Kaplan–Meier survival curves (b, e), and spider plots of individual tumor growth curves (c, f) are shown. cGAMP-PC7A NP treatment confers immune protection, rendering 4 / 7 MC38 mice tumor free, and further synergizes with anti-PD1 to achieve 100% cure rate in the MC38 model. In tumor growth studies, values represent mean ± SEM, Two-tailed Student’s t-test. In survival studies, Two-tailed Mantel– Cox test. ns, not significant; *, P < 0.05, **, P < 0.01, ***, P < 0.001 versus 5% glucose group.

[0137] The antitumor efficacy of IT injected ONM-501 as a monotherapy or in combination with anti-PD-1 was also demonstrated in a panel of 4 murine syngeneic models (MC38, CT26, B16F10, and A20), OncoNano Study (501-PD-0032021) as shown in FIG.2. ONM-501 monotherapy showed improved tumor growth inhibition (TGI) and survival in all 4 models compared with vehicle control or cGAMP alone, and the ONM-501 / anti-PD1 combination showed additional efficacy improvement with complete / durable remission and long-term survival achieved in 3 / 10, 4 / 10, 5 / 10, and 8 / 10 animals in MC38 and CT26 (colorectal), B16F10 (melanoma) and A20 models (lymphoma), respectively (Figure 1) Details on these and other studies supporting the efficacy of ONM-501 as a monotherapy and in combination can be found in the Investigator’s Brochure. EXAMPLE 1

[0138] This Phase 1, multi-center trial will consist of three parts as depicted above in FIG.3: monotherapy dose escalation; combination therapy dose finding; and combination therapy dose expansion exploring two doses in specific tumor indication(s). Each dosing cycle of ONM- 501 will be 21 days. ONM-501 will be administered as intratumoral injections once per week for three weeks (on Days 1, 8, and 15), followed by three weeks without ONM-501 administration. The monotherapy dose escalation will utilize an accelerated titration method (Simon 1997, Ivy 2010). Using this method, dose levels 1 and 2 may be evaluated in a minimum of single patient cohorts. The utilization of an accelerated titration design will minimize patient exposure at the lowest dose cohorts, and is informed by the safety profile of other, prior intratumoral STINGAttorney Docket No.100007_00059 agonists, which showed minimal systemic toxicity and dose-limiting toxicities generally related to local, mechanical reactions (Harrington 2018, Meric-Bernstam 2022). At the Sponsor’s discretion, up to three patients may be enrolled in dose levels 1 and / or 2 (using a staggered dosing methodology with no less than 3 days between Cycle 1 Day 1 dosing of patients at that dose level). In the presence of a DLT in either of the first two dose cohorts, the continuation rules of a 3+3 cohort will be followed. Subsequent dose cohorts (Dose level 3 and above) will be enrolled and proceed with dose escalation following a traditional 3+3 model. At the Sponsor’s discretion, additional patients may be added to backfill cohorts. At all dosing levels, in order to protect and prioritize patient safety, patients will be dosed in a staggered fashion, as described above. Patients will be monitored for 6 hours after dosing and return for evaluation ~24 hours after the first dose. Dosing of subsequent cohorts will occur once the DLT window (28 days) has been cleared and the CRC has confirmed continuation of dose escalation. The primary endpoint for this phase will be safety of the monotherapy and recommended doses for expansion (RDEs). Secondary endpoints for this phase will be PK, and exploratory endpoints will include evaluation of PD, and assessment of changes in systemic serum cytokines. Part 1b – ONM-501 in Combination with cemiplimab (Libtayo®)

[0139] Once the third dosing cohort of the monotherapy phase has been cleared (0 of 3 or <2 of 6 patients experiencing a DLT), the combination dose finding portion of this study can be initiated. As with the monotherapy dose finding, the primary endpoint of this phase is safety and identification of dose-limiting toxicities. Each dosing cycle of ONM-501 will be 21 days. ONM- 501 will be administered as intratumoral injections once per week for three weeks (on Days 1, 8, and 15), followed by three weeks without ONM-501 administration. The combination agent will be administered according to standard protocol, once every three weeks. This phase will evaluate ONM-501 in combination with approved immune checkpoint inhibitor (ICI) cemiplimab. Enrollment in this phase will follow a “Rolling 6” or 6+0 methodology – up to 6 patients will be enrolled in a staggered format (with no less than 3 days between Cycle 1 Day 1 dosing of patients at that dose level); dose escalation of ONM-501 will be permitted if <2 patients experience DLTs (Skolnik 2008). At the Sponsor’s discretion, additional patients may be added to backfill cohorts or evaluate additional dose levels. This dose finding will evaluate at least 2 dose levels of ONM- 501 in combination with the standard, approved dose of the ICI. If two dose levels of combination therapy are “cleared” (< 2 DLTs), both dose levels will be advanced into the expansion phase as Recommended Doses for Expansion (RDEs). If neither dose level is cleared, a -1-dose level for the combination therapy will be explored. If this -1-dose level is cleared, this will be the sole recommended dose for expansion (RDE) and expansion will utilize only this dose level. If no dose level of combination therapy is determined to be safe, only the two highest monotherapy dose levels cleared will be the RDEs and both will be taken forward to the expansion phase.Attorney Docket No.100007_00059 Part 2 –RDE ONM-501 in Combination with cemiplimab (Libtayo®) in indication-specific expansion cohorts

[0140] Once the recommended doses for expansion (RDEs) are determined for ONM- 501 + ICI combination or ONM-501 monotherapy, the expansion phase of this study will be initiated. The expansion phase will enroll patients in one to three indication-specific expansion cohorts. The rationale, objectives and assessments performed in each of these expansion cohorts is described in the appendices of this protocol. Which and how many of the expansion cohorts are opened once the RDEs are identified will be determined by the Sponsor, in collaboration with investigators, based on the totality of safety, PK, and any observed efficacy, as well as review of contemporary literature. Each cohort will enroll up to 40 patients in a specific indication to be determined by evaluation of patient profiles from the dose finding portions of this study, as well as review of pre-clinical information and contemporary literature to identify tumor types most likely to respond to combined STING agonism with checkpoint inhibition. Cohorts of the second and subsequent indications will be opened if supported by the data described above. In this part of the study, 20 patients will be enrolled in a randomized fashion to each of two ONM-501 dose levels in combination with ICI (if permitted by safety findings in the second phase). As a Phase 1b study, the primary endpoint will continue to be safety and tolerability, with evaluation of cytokines and other pharmacodynamic markers. After 20 patients are enrolled and evaluable across the two dose levels, the overall safety profile of the combination, as well as any evidence of early efficacy will be evaluated. Based on this evaluation, one of the arms may be expanded to enroll a subsequent 20 patients (total = 40) at the safest and most efficacious (i.e., “optimized”) dose. No indication will enroll more than 40 patients at any dose level without further discussion with the Agency. Number of Subjects

[0141] In Part 1a, approximately 10 patients are anticipated, with a minimum of 5 patients enrolled before opening combination therapy arm.

[0142] In Part 1b, a minimum of 12 to 18 patients are anticipated if all planned escalations are required.

[0143] In Part 2, up to 160 patients may be enrolled across selected indications. Treatment Assignment Inclusion Criteria Patients must meet all of the following criteria to be enrolled in this study: 1. Ability to understand and willingness to sign written informed consent beforperformance of any study procedures 2. Age ≥ 18 yearsAttorney Docket No.100007_00059 3. ECOG of 0-1 4. Histologically confirmed diagnosis of Follicular Lymphoma (FL), High Grade B- cell (HGBL) Lymphoma or Diffuse Large C-cell Lymphoma (DLBCL). The lymphoma must have progressed on or after at least two regimens containing cytotoxic chemotherapy, at least one of which must have contained an anti-CD20 antibody (rituximab or obinatuzumab). 5. Participants may have received chimeric antigen receptor T-cell therapy (CAR-T) but must have documented progressive disease at least 8 weeks after CAR-T infusion. 6. Participants must have a minimum of one injectable lesion which is also accessible for biopsy a. An injectable lesion is defined as being measurable (as defined by RECIST v1.1) and accessible for injection as judged by the investigator. Lesions selected for injection must not be too close to a major vessel and not be associated with increased risk of bleeding. 7. Participants with Hepatitis B Virus (HBV) that are surface antigen positive (HBsAg (+)) or Hepatitis C Virus that are antibody positive (HCV Ab +) are eligible if they have adequate liver function, controlled infection, and: a. For participants with HBV: serum hepatitis B virus DNA polymerase chain reaction (PCR) is below the limit of detection AND are receiving anti-viral therapy for Hepatitis B) b. For participants with HCV Ab +: HCV RNA by PCR is undetectable either spontaneously or in response to a successful prior course of anti-HCV therapy 8. Participants with human immunodeficiency virus (HIV) are eligible if on established HAART for a minimum of 4 weeks prior to enrollment, have an HIV viral load <400 copies / mL, and have CD4+ T-cell (CD4+) counts ≥ 350 cells / uL 9. Adequate bone marrow function: a. Absolute neutrophil count (ANC) ≥1000 per cubic millimeter (mm3) (≥1.0*103per microliter [µL]) b. Platelets ≥75,000 / mm3 (≥75*109 per liter [L]) c. Hemoglobin ≥8.0 grams per deciliter (g / dL) 10. Adequate liver function defined by: a. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to (≤)1.5 b. Total bilirubin ≤ 1.5x upper limit of the normal range (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome c. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3x ULN (in the case of liver metastasis ≤5x ULN)Attorney Docket No.100007_00059 unless there are bone metastases. Participants with ALP values >3x ULN and known to have bone metastates can be included. Exclusion Criteria 1. Other malignancy active within the previous 2 years except for those with almost no possibility of recurrence, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast that has completed curative therapy. 2. Major surgery within 4 weeks before the first dose of study drug. 3. Primary CNS lymphoma or dissemination of disease into the CNS or CSF. 4. Prolongation of corrected QT (QTc) interval to >470 millisecond (ms) for males and females when electrolytes balance is normal. 5. Females who are breastfeeding or pregnant at screening or baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 units per liter (IU / L) or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 6. Females of childbearing potential that have had unprotected sexual intercourse within 30 days before study entry and refuse to use a highly effective method of contraception (total abstinence [if it is their preferred and usual lifestyle], a contraceptive implant, an oral contraceptive, or have a vasectomized partner throughout the entire study period. 7. Male participants who are partners of women of childbearing potential and refuse to use a condom and spermicide, and whose female partners, if of childbearing potential, refuse to use a highly effective method of contraception beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period. 8. Has failed to recover from the reversible effects of prior anticancer therapy; patients with treatable adverse effects such as hypothyroidism or hypertension may be enrolled if the adverse effect is well controlled with treatment 9. Has uncontrolled or poorly controlled hypertension as defined by a sustained BP > 140 / 90, with or without antihypertensive treatment 10. Has received prior investigational therapy within 5 half-lives of the agent or 4 weeks before the first administration of study drug, whichever is shorterAttorney Docket No.100007_00059 11. High bleeding risk as determined by the investigator 12. Has had any major cardiovascular event within 6 months prior to study drug administration including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic event, pulmonary embolism or New York Heart Association Class III or IV heart failure 13. Has known hypersensitivity to any component in the formulation of ONM-501 14. Has an active infection requiring systemic treatment 15. Is participating in another therapeutic clinical trial 16. Has known hypersensitivity to any component in the formulation of cemiplimab 17. Has any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Patients with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll 18. Has a condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to administration of the first dose of ONM-501 and cemiplimab or ONM-501 monotherapy. Inhaled steroids and adrenal replacement steroid doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 19. Participants who have permanently discontinued anti-cancer immune modulating therapies due to drug-related toxicity. 20. Known history of, or any evidence of, interstitial lung disease, or active, non-infectious pneumonitis (within the past 5 years). A history of radiation pneumonitis in the radiation field is permitted. Part 1a – ONM-501 Single Agent

[0144] Following confirmation of eligibility, patients will be sequentially assigned to the next open dose cohort. The initial dose cohort will begin treatment at a dosage of 600 μg as described in the following table: Dose Level Total Dose Total Injection Number of InjectedAttorney Docket No.100007_00059 Volume Lesions -1 60 µg 100 µl 1 1 600 µg 100 µl 1 2 1200 µg 200 µl 1 3 1800 µg 300 µl 1 4 3600 µg 2 x 300 µl Up to 2 5 5400 µg 3 x 300 µl Up to 3 6 7200 µg 4 x 300 µl Up to 4 Part 1b– ONM-501 in Combination with Cemiplimab

[0145] Following confirmation of eligibility, patients will be sequentially assigned a dose ONM-501 at the next open dose cohort. Six patients will be enrolled in each dose cohort. Cemiplimab will be administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks in accordance with recommended dosing. Part 2– Expansion of ONM-501 in Combination with Cemiplimab

[0146] If two RDEs have been identified in Part 1b of the study, two dose levels will be explored in the initial phase of Part 2 of this study. Each of these dose levels will enroll up to approximately 20 patients (total of 40), after which enrollment will be paused. At this enrollment pause, a Cohort Review Committee (CRC) will be convened. The CRC will be composed of investigators who have enrolled patients in this disease-specific cohort, along with representatives from the Sponsor. The CRC will evaluate the totality of the data, including safety and any evidence of efficacy (e.g., the ORR) in each of the arms comparatively. The CRC will make a recommendation to the sponsor, based on the evaluation of the data. This recommendation could be: • Expand the higher dose level of ONM-501 in combination to up to approximately 40 total patients. The higher dose of ONM-501 will be identified as the Optimal Dose for Expansion (ODE). • Expand the lower dose level of ONM-501 in combination to up to approximately 40 total patients. The lower dose of ONM-501 will be identified as the Optimal Dose for Expansion (ODE). • Continue observation of enrolled patients without enrolling more patients to permit more time to aid differentiating between the two regimens. • Discontinue any further enrollment for a non-favorable benefit-risk ratio. If the evaluation of the two cohorts yields a comparison that is very similar between the two dose levels on both efficacy and safety, the lower dose will be expanded as the ODE.Attorney Docket No.100007_00059

[0147] Following confirmation of eligibility, patients in selected indication will be randomly assigned a dose of ONM-501 at one of two dose levels until the identification of the optimal dose for expansion. A minimum of 20 patients will be evaluated in each cohort, with a potential for up to 40 patients. Cemiplimab will be administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks in accordance with recommended dosing.

[0148] It 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 to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. SEQ ID NO: 1 (162) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQ LENGTH: 117 APGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTL TYPE: PRT YLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 HCVR SEQ ID NO: 2 (170) DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPG LENGTH: 107 KAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPE TYPE: PRT DFATYYCQQSSNTPFTFGPGTVVDFR ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 LCVR SEQ ID NO: 3 (164) GFTFSNFG LENGTH: 7 TYPE: PRT ORGANISM: Artificial SequenceAttorney Docket No.100007_00059 OTHER INFORMATION: Sythetic R2810 HCDR1 SEQ ID NO: 4 (166) ISGGGRDT LENGTH: 8 TYPE: PRT ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 HCDR2 SEQ ID NO: 5 (168) VKWGNIYFDY LENGTH: 10 TYPE: PRT ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 HCDR2 SEQ ID NO: 6 (172) LSINTF LENGTH: 6 TYPE: PRT ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 LCDR1 SEQ ID NO: 7 (174) AASAttorney Docket No.100007_00059 LENGTH: 3 TYPE: PRT ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 LCDR2 SEQ ID NO: 8 (176) QQSSNTPFT LENGTH: 9 TYPE: PRT ORGANISM: Artificial Sequence OTHER INFORMATION: Sythetic R2810 LCDR3 SEQ ID NO: 9 (330) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQ LENGTH: 444 APGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTL TYPE: PRT YLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAST ORGANISM: Artificial KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA Sequence LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHK OTHER PSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL INFORMATION: MISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR Sythetic EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT R2810 HC VR-1-117; ISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA constant-118-444 VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 10 (331) DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPG LENGTH: 214 KAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDF TYPE: PRT ATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPPSDEQ ORGANISM: Artificial LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE Sequence QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKAttorney Docket No.100007_00059 OTHER SFNRGEC INFORMATION: Sythetic R2810 LC VR-1-108; constant-109-214

Claims

Attorney Docket No.100007_00059 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer comprising administering to a patient in need thereof: (i) a sting activating micelle composition comprising: (a) a block copolymer of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof: O O Ory1X, wherein:n1is an integer from 10-200; x1is an integer from 20-300; y1is an integer from 0-10; X is a halogen, -OH, or -C(O)OH; R1and R2are each independently hydrogen or optionally substituted C1-C6alkyl; R3and R4are each independently an optionally substituted C1-C6alkyl, C3-C10cycloalkyl or aryl; or R3and R4are taken together with the corresponding nitrogen to which they are attached form an optionally substituted 5 to 7-membered ring; R5is hydrogen or -C(O)CH3; and (b) a non-peptide STING agonist; and (ii) a sting activating micelle composition comprising: an anti-PD1 composition comprising an isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human programmed death-I (PD-1) protein, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (CDRs) (HCDRl, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) sequence of SEQ ID NO:1; and three light chain CDRs (LCDRl, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) sequence of SEQ ID NO:

2.

2. The method of claim 1, wherein the sting activating block copolymer of Formula (I) has the structure of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or hydrate thereof:Attorney Docket No.100007_00059 .

3. The method of any one of claims 1–2, wherein the cyclic dinucleotide STING agonist is a compound having the structure of Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt, solvate or hydrate thereof: , whereinA1and A2are each independently OH or SH; B1and B2are each independently guanine or adenine; R10is H, halogen, OH, OCH3; and R11is halogen or OH.

4. The method of any one of claims 1–2, wherein the cyclic dinucleotide STING agonist is cGAMP.

5. The method of any one of claims 1–4, wherein the sting activating micelle composition is administered at a dose 1200 ug-7200 µg.

6. The method of any one of claims 1–5, wherein the sting activating micelle composition is administered once a week over at least a three week period.Attorney Docket No.100007_00059 7. The method of any one of claims 1–6, wherein the anti-PD1 composition is administered at a dose of 350 mg.

8. The method of any one of claims 1–7, wherein the anti-PD1 composition is administered once in a three-week period.

9. The method of any one of claims 1–8, wherein the isolated antibody or antigen-binding fragment thereof, comprises: (a) a HCDR1 domain having an amino acid sequence of SEQ ID NO:3; (b) a HCDR2 domain having an amino acid sequence of SEQ ID NO:4; (c) a HCDR3 domain having an amino acid sequence of SEQ ID NO:5; (d) a LCDR1 domain having an amino acid sequence of SEQ ID NO:6; (e) a LCDR2 domain having an amino acid sequence of SEQ ID NO:7; and (f) a LCDR3 domain having an amino acid sequence of SEQ ID NO:

8.

10. The method of claim 9, wherein the antibody or antigen-binding fragment thereof comprises a HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2.

11. The method of claim 9, wherein the antibody or antigen-binding fragment thereof has one or more of the following properties: (a) blocks human PD-1 protein binding to PD-L1 with an IC50of less than 3 nM as measured in a competition sandwich ELISA assay at 25° C.; (b) binds monomeric human PD-1 with a binding dissociation equilibrium constant (KD) of less than about 50 nM as measured in a surface plasmon resonance assay at 37° C.; (c) binds monomeric human PD-1 with a KDless than about 12 nM in a surface plasmon resonance assay at 25° C.; (d) binds monomeric cynomolgus PD-1 with a KDless than about 8.5 nM in a surface plasmon resonance assay at 25° C.; (e) binds monomeric human PD-1 with a dissociative half-life (t½) of greater than about 6.3 minutes as measured in a surface plasmon resonance assay at 25° C.; andAttorney Docket No.100007_00059 (f) binds monomeric human PD-1 with a dissociative half-life (t½) of greater than about 0.9 minutes as measured in a surface plasmon resonance assay at 37° C.

12. The method of claim 11, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence of SEQ ID NO:

9.

13. The method of claim 11, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the light chain comprises an amino acid sequence of SEQ ID NO:

10.

14. The method of claim 13, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain / light chain amino acid sequence pair of SEQ ID NO:9 / 10.

15. The method of any of claims 1–14, wherein the anti-PD1 composition is cemiplimab.

16. The method of any of claims 1–15 comprising administering over a three week period to a patient in need thereof: (i) a 1200 µg – 7200 µg weekly dose of the sting activating micelle composition; and (ii) a 350 mg dose of the anti-PD1 composition once in the three-week period.

17. The method of any of claims 1–16, wherein the anti-PD1 composition is present in an amount of 350 mg / 7mL (50 mg / mL).

18. The method of any of claims 1–17, wherein the sting activating micelle composition is present in an amount of 600 µg / 100 µL.

19. The method of any of claims 1–18, wherein the weekly dose of sting activating micelle is 1,200, 1,800, 3,600, 5,400 or 7,200 µg.

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