PARP7 inhibitors

Abstract

To provide improved PARP7 inhibitors for treating cancers.SOLUTION: Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or a deuterated analogue thereof, pharmaceutical compositions comprising a compound of this invention together with a pharmaceutically acceptable excipient thereof, and methods of treating cancer therewith.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 304,493, filed January 28, 2022, U.S. Provisional Patent Application No. 63 / 378,647, filed October 6, 2022, and U.S. Provisional Patent Application No. 63 / 385,303, filed November 29, 2022, each of which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] Adenosine diphosphate (ADP)-ribosylation is a well-conserved post-translational modification found in viruses, bacteria, and eukaryotes. This modification is catalyzed by members of the ART superfamily of proteins, which transfer ADPr from nicotinamide adenine dinucleotide (NAD+) to a substrate via an N-, O-, or S-glycosidic bond on the target molecule. A subset of ARTs are poly(adenosine diphosphate-ribose) polymerases (PARPs), which are members of a family of 17 known enzymes that regulate fundamental cellular processes, including gene expression, protein degradation, and multiple cellular stress responses (M.S. Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat. Chem. Biol. 14, 236-243 (2018)). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and a novel approach for novel therapeutic agents.

[0003] Of particular interest is 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TIPARP), a CCCH-type zinc finger domain-containing protein (Proc. Nat. Acad. Sci. 114(10)2681-2686(2017)). TIPARP is also known as PARP7 and ARTD14. PARP7 acts as a negative regulator of specific aryl hydrocarbon receptor (AHR) transcriptional targets. AHR is then activated by many substrates, including cigarette smoke. PARP7 inhibitors have been shown to restore type I interferon (IFN) signaling responses to nucleic acids and induce tumor regression in an immunocompetent BALB / c mouse model bearing CT26 tumors (Gozgit, et al., Cancer Cell 39, 1214-1226(2021)).

[0004] There are currently no approved PARP7 inhibitory pharmaceuticals. It would therefore be useful to provide PARP7 inhibitor compounds with properties suitable for pharmaceutical administration to mammals, particularly humans. Therefore, there is a need for improved PARP7 inhibitors for cancer treatment. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] MSCohen,P.Chang,Insights into the biogenesis,function,and regulation of ADP-ribosylation.(Nat.Chem Biol 14,236-243(2018) [Non-patent document 2] Proc.Nat.Acad.Sci.114(10)2681-2686(2017) [Non-patent document 3] Gozgit,et al.,Cancer Cell 39,1214-1226(2021) Summary of the Invention

[0006] Compounds and pharmaceutical compositions useful as inhibitors of PARP7 are provided herein. Some compounds of the present disclosure may find use in pharmaceutical compositions, together with at least one pharmaceutically acceptable excipient, for treating a subject in need thereof.

[0007] In one embodiment of the present invention, a compound of formula (I) [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: J is [ka] and X 1 are N, C=O, CR 10 , or C-(R 10 )2, X 2 is N, NR 11 , C.R. 12 , or C-(R 12 )2, X 3 is N or CR 13 and X 4 is N or CR 13 and X 5 is N or CR 13 or A is, C, O, N, One or more R 15 3- to 10-membered cycloalkyl optionally substituted with One or more R 15 4-11 membered heterocyclyl optionally substituted with is selected from When A is O, n is 0; when A is N, n is 1; when A is C, n is 1 or 2; When A is N, n is 0 or 1, and L 1 is C or NR 17 and L 2 , L 3 and L 4 are C, respectively, L 1 , L 2 are independently C, C 6~10 aryl, 5- to 12-membered heteroaryl, or NH; L 3 and L 4 are C, respectively, or L 1 and L 2 together with the atoms to which they are attached, R 15 one or more 3 to 12-membered cycloalkyl, each optionally substituted with 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 1 and L 3 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 2 and L 3 together with the atoms to which they are attached, R 153 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 3 and L 4 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with 6~10 the aryl or 5- to 12-membered heteroaryl is monocyclic or bicyclic, or L 2 and L 4 together with the atoms to which they are attached, R 15 3 to 12 membered cycloalkyl, each optionally substituted with one or more of 6~10 The aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclic ring may be formed by one or more R 15 and C 6~10 The aryl or 5- to 12-membered heteroaryl may be one or more R 15 and wherein each is a monocyclic or bicyclic ring optionally substituted with ; R 1 H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR 14 , C(O)-R 14 , -SF5;C(O)-N(R17 )(R 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 15 , N(R 17 )C(O)OR 15 , N(R 7 )S(O)2(R 15 ), N(R 17 )C(O)-N(R 17 )(R 18 ), S(O)2R 15 , S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , One or more R 15 C optionally substituted with 1~5 alkyl; or One or more R 15 C optionally substituted with 3~10 cycloalkyl; or One or more R 15 5-10 membered optionally substituted with heteroaryl; or One or more R 15 C optionally substituted with 6~10 aryl; or One or more R 15 4-7 membered optionally substituted with Heterocyclyl is selected from R 2 is H, C1-9 alkyl, C 2~9 Alkenyl, or C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 10 and optionally substituted with R 3 and R 4 are each independently H, C1-9 alkyl, C 2~9 Alkenyl, C 2~9alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 15 , one or more R 15 C optionally substituted with 3~12 cycloalkyl, one or more R 15 C optionally substituted with 6~10 Aryl, one or more R 15 4- to 11-membered heterocyclyl optionally substituted with, or one or more R 15 Any optionally substituted with an optionally substituted 5-10 membered heteroaryl; or R 2 and R 3 together with the atoms to which they are attached, R 15 forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle optionally substituted with one or more of A 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl may be one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with R 3 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with R 2 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 and wherein the ring structure is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring structure, each optionally substituted with R 5a , R 5bR 6a , R 6b , R 7a R 7b are each independently H, halo, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 One or more R 15 C optionally substituted with 1~9 alkyl; One or more R 15 C optionally substituted with 2~9 Alkynyl; One or more R 15 C optionally substituted with 2~9 Alkenyl; One or more R 15 5-12 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; One or more R 15 4- to 12-membered heterocyclyl optionally substituted with One or more R 15 C optionally substituted with 3~12 cycloalkyl or R 5a and R 5btogether with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R 6a and R 6b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R7 a and R 7b together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with Z is H, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~8 Haloalkyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -OC(O)(C 1~9 alkyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkynyl), -OC(O)(C 3~15 cycloalkyl), -OC(O)(C 1~8 haloalkyl), -OC(O)(C 6~10 aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl)2, -N(C 6~10 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 6~10 aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl). , one or more R 13 5-12 membered heteroaryl substituted with; One or more R 15 C optionally substituted with 6~10 Aryl; one or more R 15 C optionally substituted with 3~12 cycloalkyl; one or more R 15 4-12 membered heterocyclyl substituted with and optionally substituted with wherein any 5- to 12-membered heteroaryl, C 6~10 Aryl, C 3~12 Cycloalkyl or 4- to 12-membered heterocyclyl may be one or more R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each substituted with R 10 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 Aryl, 5-10 membered Heteroaryl or 4-12 membered and heterocyclyl, wherein any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 11 is H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 6- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 one or more and optionally substituted with R 12 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R18 ), S(O)2R 16 , S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, S(O)2R 16 , S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16and optionally substituted with one or more of: R 15 are independently H, C=O, hydroxy, halo, -NO2-N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -OC(O)(C 1~9 alkyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkynyl), -OC(O)(C 3~15 cycloalkyl), -OC(O)(C 1~8 haloalkyl), -OC(O)(C 6~10 aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 cycloalkyl)2, -N(C 1~8 haloalkyl)2, -N(C6~10 -N(aryl), -N(5- to 12-membered heteroaryl), -N(4- to 12-membered heterocyclyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 Cycloal Kill), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 6~10aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl) -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5~ 12-membered heteroaryl), -NHC(O)O(4- to 12-membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl). R 16 are independently H, C=O, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OH, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2-N(C 3~15 cycloalkyl)2-N(C 2~6 alkenyl)2-N(C 2~6 alkynyl)2-N(C 3~15 cycloalkyl)2-N(C 1~8 haloalkyl)2-N(C 6~10 aryl)2-N(5-12-membered heteroaryl)2-N(4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 6~10 aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O )O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5- to 12-membered heteroaryl), -S(4- to 12-membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(NH)(C 3-9 cycloalkyl), -S(O)(C 1~9 Alkyl)(C 1~9alkyl), -S(O)(NH)(C 6~10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl), and R 17 and R 18 are independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 is optionally substituted with one or more having In one embodiment of the present invention, a compound represented by formula (Ia) [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: J is [ka] and X 1 are N, C=O, CR 10 , or C-(R 10 )2, X 2 is N, NR 11 , C.R. 12 , or C-(R 12 )2, X 3 is N or CR 13 and X 4 is N or CR 13 and X 5 is N or CR 13 or A is, C, O, N, One or more R 15 3 to 10-membered cycloalkyl optionally substituted with One or more R 15 4-11 membered heterocyclyl optionally substituted with is selected from When A is O, n is 0; when A is N, n is 1; when A is C, n is 1 or 2; R 1 H, halo, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, CN, OR 14 , C(O)-R 14 , -SF5;C(O)-N(R 17 )(R 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 15 , N(R 17 )C(O)OR 15 , N(R 7 )S(O)2(R 15 ), N(R 17 )C(O)-N(R 17 )(R 18 ), S(O)2R 15, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 One or more R 15 C optionally substituted with 1~5 alkyl; or One or more R 15 C optionally substituted with 3~10 cycloalkyl; One or more R 15 5-10 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; or One or more R 15 4- to 7-membered heterocyclyl optionally substituted with is selected from R 2 is H, C1-9 alkyl, C 2~9 Alkenyl, or C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 10 in is optionally substituted, R 3 and R 4 are each independently H, C1-9 alkyl, C 2~9 Alkenyl, C 2~9 alkynyl, wherein any alkyl, alkenyl, and alkynyl is selected from one or more R 15 , one or more R 15 C optionally substituted with 3~12 cycloalkyl, one or more R 15 C optionally substituted with 6~10 Aryl, one or more R 15 4- to 11-membered heterocyclyl optionally substituted with, or one or more R 15 optionally substituted with a 5-10 membered heteroaryl optionally substituted with R 2 and R 3together with the atoms to which they are attached, R 15 forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle optionally substituted with one or more of A 4- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl may be one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring optionally substituted with R 3 and R 4 together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with R 5a , R 5b R 6a , R 6b , R 7a R 7b are each independently H, halo, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 One or more R 15 C optionally substituted with 1~9alkyl; One or more R 15 C optionally substituted with 2~9 Alkynyl; One or more R 15 C optionally substituted with 2~9 Alkenyl; One or more R 15 5-12 membered heteroaryl optionally substituted with One or more R 15 C optionally substituted with 6~10 aryl; One or more R 15 4- to 12-membered heterocyclyl optionally substituted with One or more R 15 C optionally substituted with 3~12 cycloalkyl or R 5a and R 5b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R 6a and R 6b together with the atoms to which they are attached, R 15 or forming a 3- to 12-membered cycloalkyl or 4- to 12-membered heterocycle, each optionally substituted with one or more of R7 a and R 7b together with the atoms to which they are attached, R 15 and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is optionally substituted with one or more R 15 or is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each optionally substituted with Z is -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~8 Haloalkyl, -O(C1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -OC(O)(C 1~9 alkyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkynyl), -OC(O)(C 3~15 cycloalkyl), -OC(O)(C 1~8 haloalkyl), -OC(O)(C 6~10 aryl), -OC(O)(5-12 membered heteroaryl), - OC(O)(4-12 membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2-N(C 3~15 cycloalkyl)2-N(C 2~6 alkenyl)2-N(C 2~6 alkynyl)2-N(C 3~15 cycloalkyl)2-N(C 1~8 haloalkyl)2-N(C 6~10 aryl)2-N(5-12-membered heteroaryl)2-N(h 4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 6~10 aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl). , one or more R 13 5-12 membered heteroaryl substituted with; One or more R 15 C optionally substituted with 6~10 Aryl; one or more R 15 C optionally substituted with 3~12 cycloalkyl; one or more R 15 4-12 membered heterocyclyl substituted with and optionally substituted with wherein any 5- to 12-membered heteroaryl, C 6~10 Aryl, C 3~12 Cycloalkyl or 4- to 12-membered heterocyclyl may be one or more R 15and the 3- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl is substituted with one or more R 15 is a monocyclic, bicyclic, fused bicyclic, spirocyclic or bridged ring, each substituted with R 10 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , -SF5, S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 Aryl, 5-10 membered Heteroaryl or 4-12 membered and heterocyclyl, wherein any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 11 is H, C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 6- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl; Here, any alkyl, alkenyl, cycloalkyl, aryl, heterocyclic aryl or heterocyclyl is R 16 and optionally substituted with one or more of: R 12 H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R1 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17 )C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), S(O)2R 16 , S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 and optionally substituted with one or more of: R 13 are independently H, halo, CH3, CH2F, CHF2, CF3, CH2CF3, OCH3, OCF3, OCHF2, NO2, CN, OR 14 , C(O)-R 16 , C(O)-N(R 17 )(R 18 ), N(R 17 )(R 18 ), N(R 17 )C(O)-R 16 , N(R 17)C(O)OR 14 , N(R 17 )S(O)2(R 16 ), -N(R 17 )C(O)-N(R 18 )(R 18 ), -SF5, S(O)2R 16 , S(O)2N(R 17 )(R 18 ), S(O)(NH)R 17 , S(O)(NR 17 )NR 18 , C1-9 alkyl, C2-9 alkenyl, C2-9 alkynyl, C 3~12 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl; where any alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is R 16 and optionally substituted with one or more of: R 15 are independently H, C=O, hydroxy, halo, -NO2-N3, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -OC(O)(C 1~9 alkyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkenyl), -OC(O)(C 2~6 alkynyl), -OC(O)(C 3~15 cycloalkyl), -OC(O)(C1~8 haloalkyl), -OC(O)(C 6~10 aryl), -OC(O)(5-12 membered heteroaryl), -OC(O)(4-12 membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2-N(C 3~15 cycloalkyl)2-N(C 2~6 alkenyl)2-N(C 2~6 alkynyl)2-N(C 3~15 cycloalkyl)2-N(C 1~8 haloalkyl)2-N(C 6~10 aryl)2-N(5-12-membered heteroaryl)2-N(h 4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10-C(O)(aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl) , -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 6~10 aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl) -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5-12 membered heteroaryl), -S(4-12 membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, where R 15 Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~ 8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl). R 16 are independently H, C=O, halo, -NO2, -CN, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, -OH, -O(C 1~9 alkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10 aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), -NH2-NH(C 1~9 alkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6~10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2-N(C 3~15 cycloalkyl)2-N(C 2~6 alkenyl)2-N(C 2~6 alkynyl)2-N(C3~15 cycloalkyl)2-N(C 1~8 haloalkyl)2-N(C 6~10 aryl)2-N(5-12-membered heteroaryl)2-N(4-12-membered heterocyclyl)2-N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(5-12 membered heteroaryl), -N(C 1~9 alkyl)(4-12 membered heterocyclyl), -C(O)(C 1~9 alkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 cycloalkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 6~10 aryl), -C(O)(5-12 membered heteroaryl), -C(O)(4-12 membered heterocyclyl), -C(O)O(C 1~9 alkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 6~10 aryl), -C(O)O(5-12 membered heteroaryl), -C(O)O(4-12 membered heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(C1~8 haloalkyl), -C(O)NH(C 6~10 aryl), -C(O)NH(5- to 12-membered heteroaryl), -C(O)NH(4- to 12-membered heterocyclyl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 6~10 aryl), -C(O)N(5- to 12-membered heteroaryl), -C(O)N(4- to 12-membered heterocyclyl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 6~10aryl), -NHC(O)NH(5- to 12-membered heteroaryl), -NHC(O)NH(4- to 12-membered heterocyclyl), -SH, -S(C 1~9 alkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 cycloalkyl), -S(C 1~8 haloalkyl), -S(C 6~10 aryl), -S(5- to 12-membered heteroaryl), -S(4- to 12-membered heterocyclyl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)(NH)(C 3-9 cycloalkyl), -S(O)(C 1~9 Alkyl)(C 1~9 alkyl), -S(O)(NH)(C 6~10 aryl), -S(O)(NH)(5-12 membered heteroaryl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 cycloalkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 6~10 aryl), -S(O)(5-12 membered heteroaryl), -S(O)(4-12 membered heterocyclyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more halo, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C 1~9 alkyl), -NH(C 3~15 cycloalkyl), -NH(C 1~8 haloalkyl), -NH(C 6-10 aryl), -NH(5- to 12-membered heteroaryl), -NH(4- to 12-membered heterocyclyl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 6~10 aryl), -NHC(O)(5-12 membered heteroaryl), -NHC(O)(4-12 membered heterocyclyl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(5-12 membered heteroaryl), -NHC(O)O(4-12 membered heterocyclyl), -NHC(O)NH(C 1~9 alkyl), -S(O)(NH)(C 1~9 alkyl), -S(O)2(C 1~9 alkyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 6~10 aryl), -S(O)2(5-12 membered heteroaryl), -S(O)2(4-12 membered heterocyclyl), -S(O)2NH(C 1~9 alkyl), -S(O)N(C 1~9 alkyl)2, -O(C 3~15 cycloalkyl), -O(C 1~8 haloalkyl), -O(C 6~10aryl), -O(5- to 12-membered heteroaryl), -O(4- to 12-membered heterocyclyl), or -O(C 1~9 alkyl), and R 17 and R 18 are independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3~15 Cycloalkyl, C 6~10 aryl, 5- to 12-membered heteroaryl, or 4- to 12-membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from R 16 is optionally substituted with one or more having

[0008] Also provided are pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, together with a pharmaceutically acceptable excipient.

[0009] Further provided is a method of treating cancer in a subject in need thereof, comprising administering to the patient a compound of the invention or a pharmaceutical composition comprising a compound of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0010] I. Definition The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0011] The following description sets forth example methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0012] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0013] Wavy line [ka] indicates the point of attachment. "C u~v The prefix "" indicates that the following group has carbon atoms u through v. For example, "C 1~6 "Alkyl group" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0014] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, for that term, "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0015] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, ne Examples of alkyl groups include dipentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can be included, so for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2)).

[0016] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or having 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0017] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or having 2 to 4 carbon atoms (i.e., C 2~4"alkynyl" refers to an alkyl group. The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0018] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0019] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms have been replaced by a halogen.

[0020] "Alkylthio" refers to the group "alkyl-S-".

[0021] "Amino" is the group -NR y R y where each R y is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0022] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to a group having 6 to 20 carbon ring atoms (i.e., C 6~20 aryl), having 6 to 12 carbon ring atoms (i.e., C 6~10 aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10(aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0023] "Cyano" refers to the group --CN.

[0024] "Keto" refers to the group C=O.

[0025] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the group, and -NR y C(O)OR z "N-carbamoyl group" refers to both the "N-carbamoyl group" and the "N-carbamoyl group" y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl, each of which can be optionally substituted.

[0026] "Carboxyl" refers to -C(O)OH.

[0027] "Ester" refers to both -OC(O)R and -C(O)OR, where R is a substituent, each of which can be optionally substituted as defined herein.

[0028] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms have been replaced by a halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0030] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH, -CHOCH, -SCH, -CHSCH, -NRCH, and -CHNRCH, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0031] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a group having 1 to 20 ring carbon atoms (i.e., C 1~20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 heteroaryl), or 3 ~8 carbon ring atoms (i.e., C 3~8Heteroaryl) and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via any ring of the fused system. Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered heteroaryl regardless of attachment to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0032] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bicyclic heterocyclyl groups, bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of attachment (i.e., it can be attached via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass rings in which any non-aromatic ring containing at least one heteroatom may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl has 2 to 20 ring atoms (i.e., 4-20-membered heterocyclyl), 2 to 12-membered heterocyclyl, 4 to 10 ring atoms (i.e., 4-10-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4-8-membered heterocyclyl), or 4 to 6 ring carbon atoms (i.e., 4-6-membered heterocyclyl), and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. The heterocyclyl may contain one or more C=O and / or thioC=O groups. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, diC=Oranyl, azetidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 4- to 7-membered sultam, 4- to 7-membered cyclic carbamate, 4- to 7-membered cyclic carbonate, 4- to 7-membered cyclic sulfide, and morpholinyl.As used herein, the term "bridged heterocyclyl" refers to a 4- to 10-membered ring moiety in which two non-adjacent atoms of a heterocyclyl having one or more (e.g., one or two) 4- to 10-membered ring moieties are connected, each heteroatom independently, to at least one heteroatom selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term "spiroheterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein the one or more additional rings are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, and wherein a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include 1,2,3,4-tetrahydroisoquinolinyl, 1-C=O-1,2,3,4-tetrahydroisoquinolinyl, 1-C=O-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoi. Examples of heterocyclyls include, but are not limited to, thiamin, thiamin, and thiamin, and heterocyclyls can be attached via either ring of the fused system. As used herein, a bicyclic heterocyclyl group is a heterocyclyl group attached at two points to another ring group, which may itself be a heterocyclic or carbocyclic group.

[0033] As used herein, the term "nitrogen- or sulfur-containing heterocyclyl" refers to a heterocyclyl moiety containing at least one nitrogen atom or at least one sulfur atom, or both nitrogen and sulfur atoms, within the ring structure. It is understood that other heteroatoms, including oxygen, may be present in addition to nitrogen, sulfur, or a combination thereof. Examples of nitrogen- or sulfur-containing heterocyclyls include morpholinyl, thiomorpholinyl, thiazolyl, isothiazolyl, oxazolidinone 1,2-dithiolyl, piperidinyl, piperazinyl, and the like.

[0034] "Hydroxy" or "hydroxyl" refers to the group -OH. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms has been replaced by hydroxyl.

[0035] "Nitro" refers to the -NO2 group.

[0036] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or defined group.

[0037] "Alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or defined group.

[0038] "Alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or defined group.

[0039] "Thiocyanate" -SCN.

[0040] "Thiol" refers to the group -SR, where R is a substituent or defined group.

[0041] "ThiC=O" or "thione" refers to the (=S) or (S) group.

[0042] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as one moiety, e.g., arylalkyl, the last-mentioned group contains the atom by which the moiety is attached to the remainder of the molecule.

[0043] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety. "Optionally substituted" may be from 0 to the maximum number of possible substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must be on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from the (required) substitution.

[0044] When a moiety is "optionally substituted" and reference is made to any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," this general term includes (C- 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), O-(C 3~10

[0033] The term "any heterocyclyl" can refer to any preceding specifically recited term, such as aryl, cycloalkyl, or aryl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryl such as phenyl or naphthyl. Also, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyl such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl, and the like. Similarly, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heterolyl)," as well as specific heteroaryls such as pyridine.

[0045] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0046] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 These are compounds into which a radioactive isotope, such as 1C, has been incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in other applications. may be useful in the radiation treatment of patients.

[0047] The present disclosure also includes "deuterated analogs" of compounds of Formula I in which 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0048] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure exhibit improved drug kinetics (DMPK) with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, etc. This may result in reduced requirements and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0049] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0050] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0051] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0052] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts containing inorganic acids and salts containing organic acids. In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN (alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines. Suitable amines include, but are not limited to, primary, secondary, and tertiary amines such as amines (i.e., NH(aryl), HN(aryl), N(aryl), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0053] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining the substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted, and those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formula herein should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds with such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that any combination of the above definitions and substituents should not result in an inoperable species or compound.

[0054] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0055] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds are also provided. Hydrates of the compounds described herein are also provided.

[0056] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when a combination of groups is referred to herein as one moiety, e.g., arylalkyl, the last-mentioned group contains the atom by which the moiety is attached to the remainder of the molecule.

[0057] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group that may or may not be replaced by a non-hydrogen moiety. "Optionally substituted" may be from 0 to the maximum number of possible substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must be on a substitutable hydrogen atom of the indicated substituent. Optional substitutions may be the same as or different from the (required) substitution.

[0058] When a moiety is "optionally substituted" and reference is made to any general term such as "alkyl," "alkenyl," "alkynyl," "haloalkyl," "cycloalkyl," "aryl," or "heteroaryl," this general term includes (C- 1~3 alkyl), (C 4~6 alkyl), -O(C 1~4 alkyl), (C 3~10 cycloalkyl), O-(C 3~10

[0033] The term "any heterocyclyl" can refer to any preceding specifically recited term, such as aryl, cycloalkyl, or aryl. For example, "any aryl" includes both "aryl" and "-O(aryl)," as well as examples of aryl such as phenyl or naphthyl. Also, the term "any heterocyclyl" includes both the terms "heterocyclyl" and "O-(heterocyclyl)," as well as examples of heterocyclyl such as oxetanyl, tetrahydropyranyl, morpholino, piperidinyl, and the like. Similarly, the term "any heteroaryl" includes the terms "heteroaryl" and "O-(heterolyl)," as well as specific heteroaryls such as pyridine.

[0059] Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that the compound includes both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0060] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125I. Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 These are compounds into which a radioactive isotope, such as C, has been incorporated. Such isotopically labeled compounds can be useful in metabolic studies, reaction kinetic studies, and single-photon emission computed tomography (PET) including drug or substrate tissue distribution assays. in detection or imaging techniques such as SPECT (scanning computed tomography), or may be useful in the radiation treatment of patients.

[0061] The present disclosure also includes "deuterated analogs" of compounds of Formula I in which 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of See "Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0062] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0063] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0064] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0065] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0066] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts containing inorganic acids and salts containing organic acids. In addition, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines

[0033] Suitable amines include, but are not limited to, primary, secondary, and tertiary amines such as (substituted alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0067] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, C=O, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar amorphous structures resulting from defining the substituents with an infinite number of additional substituents (e.g., substituted aryls with substituted alkyls, which themselves are substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of ordinary skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. Unless otherwise specified, if a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents are halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or aryl. or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. Those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formulas herein should be selected to provide compounds that are sufficiently stable to provide pharmaceutically useful compounds that can be formulated into acceptably stable pharmaceutical compositions. Compounds with such stability are considered to be within the scope of the present invention. Those skilled in the art should understand that any combination of the above definitions and substituents should not result in inoperable species or compounds.

[0068] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0069] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0070] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided. II. Combination

[0071] Patients treated by administering the PARP7 inhibitors of the present disclosure often exhibit diseases or conditions that would benefit from treatment with other therapeutic agents. These diseases or conditions may be of an oncological nature or may be associated with inflammation, metabolic disorders, gastrointestinal disorders, etc. Accordingly, one aspect of the present disclosure is a method for treating cancer, comprising administering to a subject, particularly a human subject, a compound in combination with one or more compounds useful for treating such diseases.

[0072] In some embodiments, the compounds of the present disclosure are co-formulated with one or more additional active ingredients. In some embodiments, the other active ingredients are administered approximately simultaneously in separate dosage forms. In some embodiments, the other active ingredients are administered sequentially and may be administered at different times relative to the compounds of the present disclosure.

[0073] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, the additional therapeutic agents include, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist, or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (e.g., monospecific and multispecific antibodies in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimic (e.g., adnectin, affibody molecule, affilin, affimer, affitin, etc.), ...inflammatory agent, an immunotherapeutic agent, an anti-inflammatory agent, an immunotherapeutic agent, an anti-inflammatory agent, an anti-inflammatory agent, an anti-inflammatory agent, an , alphabodies, anticalins, peptide aptamers, armadillo repeat proteins (ARMs), atrimers, avimers, designed ankyrin repeat proteins (DARPins®), finomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs, antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifying or editing agents, cells comprising chimeric antigen receptors (CARs), e.g., T cell immunotherapeutics, These include engineered T cell receptor (TCR-T) containing NK cell immunotherapeutics, or macrophage immunotherapeutics, or any combination thereof. Exemplary Targets

[0074] In some embodiments, the one or more additional therapeutic agents include, for example, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator, or suppressor of a target (e.g., a polypeptide or polynucleotide), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL gene Oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); Absent-in-melanoma 2 (AIM2; NCBI Gene ID: 9447); Acetyl-CoA acyltransferase 2 (ACAA2; NCBI Gene ID: 10499); Acid phosphatase 3 (ACP3; NCBI Gene ID: 55); Adenosine deaminase (ADA, ADA1; NCBI Gene ID: 100); Adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA 2B (A2b, A2BR), ADORA3 (A3); NCBI Gene ID: 134, 135, 136, 137); AKT serine / threonine kinase 1 (AKT1, AKT, PKB; NCBI Gene ID: 207); alanyl aminopeptidase, membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha-fetoprotein (AFP; NCBI Gene ID: 174); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC 3 (VAP1); NCBI Gene ID: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI Gene ID: 284, 285); angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); apoptosis-inducing factor mitochondrial-associated 1 (AIFM1, AIF; NCBI Gene ID: 9131);Arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asteraid homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472); ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp-protease (CLPP; NCBI Gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase lyase (AXL; NCBI Gene ID: 558); B and T lymphocyte-associated (BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing protein (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene ID: 329, 330, 331, 332); basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 682); B cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; NCBI Gene ID: 27113); BCL2-like (e.g., B; CL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene ID: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-carboxyglutamic acid protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein-10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI Gene ID: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); crosslink cluster region (BCR; NCBI Gene ID: 613); bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1001, 1004); Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363); carbonic anhydrase (CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI Gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 83 71, 11238, 23632, 56934, 377677); carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI Gene IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI Gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene IDs: 836, 840, 841, 864); catenin β1 (CTNNB1;NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC-motif chemokine ligand 21 (CCL21; NCBI Gene ID: 6366); CC-motif chemokine receptor 2 (CCR2; NCBI Gene ID: 729230); CC-motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer-binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NCBI Gene ID: 8317); cell communication network factor 2 (CCN2; NCBI Gene ID: 1490); cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatomammotropic hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18, NCBI Gene IDs: 9074, 51208);Markers of cluster of differentiation (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD3 beta (TRB), CD3 gamma (TRG), CD3 delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TN FRSF5), CD44(MIC4, PGP1), CD47(IAP), CD48(BLAST1), CD52, CD55(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7- 1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CSF1R), CD116(GMCSFR, CSF2RA), CD122(IL2RB), CD123(; IL3RA), CD128(IL8R1), CD132(IL2RG), CD135(FLT3), CD137(TNFRSF9, 4-1BB), CD142(TF, TFA), CD152(CTLA4), CD160, CD182(IL8R2), CD193( CCR3), CD194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), C CD331 (FGFR1), CD332 (FGFR2), CD333 (FGFR3), CD334 (FGFR4); NCBI Gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263 , 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); clusterin (CLU; NCBI Gene ID: 1191); coagulation factors (e.g., F7, FXA; NCBI Gene IDs: 2155, 2159); collagen type IV alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A 4, COL4A5; NCBI Gene ID: 1282, 1284, 1285, 1286, 1287); collectin subfamily member 10 (COLEC10; NCBI Gene ID: 10584); colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI Gene ID: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI Gene ID: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI Gene ID: 10987);C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI Gene ID: 160364, 170482, 283420); C-X-C motif chemokine ligand 12 (CXCL12; NCBI Gene ID: 6387); C-X-C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene ID: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI Gene ID: 595) cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI Gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI Gene ID: 900); cytochrome P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidations; reductase (POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD-box helicase (e.g., DDX5, DDX6, DDX58; NCBI Gene IDs: 1655, 1656, 23586); delta-like canonical Notch ligand (e.g., DLL3, DLL4; NCBI Gene IDs: 10683, 54567); diablo IAP-binding mitochondrial protein (DIABLO, SMAC; NCBI Gene ID: 56616); diacylglycerol kinase (e.g., DGKA, DGKZ; NCBI Gene IDs: 1606, 8525); Dickkopf WNT signaling pathway inhibitor (e.g., DKK1, DKK3; NCBI Gene ID: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI Gene ID: 780, 4921); DNA-dependent protein kinase (PRKDC; NCBI Gene ID: 5591) DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI Gene ID: 7150, 7153, 7155, 7156, 8940); dopachrome tautomer (DCT; NCBI Gene ID: 1638); dopamine receptor D2 (DRD2; NCBI Gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI Gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3, CD203c; NCBI Gene ID: 1 D:5169); EMAP-like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene ID: 51752, 64167); enhancer of zeste2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA7, EPHB4; NCBI Gene ID: 1969, 2041, 2042, 2043 , 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4); NCBI Gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epidermal mitogen (EPGN;NCBI Gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene ID: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI Gene ID: 1973, 1984); exopolitin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolysis enzyme (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene ID: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI Gene ID: 83416); fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191); fibroblast growth factor receptor (e.g., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD 333), FGFR4 (CD334); NCBI Gene ID: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5; NCBI Gene ID: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF; NCBI Gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI Gene ID: 2321, 232 2, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI Gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); flurin (flurin, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN;NCBI Gene ID: 2534); galectins (e.g., ; LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene IDs: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate transfer receptor 1 (GRM1; NCBI Gene ID: 2911); glutaminase (GLS; NCBI Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID: 29 50); glycogen synthase kinase 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI Gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID :2658); growth factor receptor-bound protein 2 (GRB2, ASH; NCBI Gene ID:2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL; NCBI Gene ID:2984); H19 imprinted maternally expressed transcript (H19; NCBI Gene ID:283120); HCK proto-oncogene, Src family tyrosine kinase (HCK; NCBI Gene ID:3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP) 78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene ID: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1(HO1), HMOX2(HO1); NCBI Gene ID: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatic growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associated 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone deacetylases (e.g., HDAC1, HDAC7, HDAC9;NCBI Gene IDs: 3065, 9734, 51564); HRas proto-oncogene, GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1); NCBI Gene IDs: 2034, 3091); I-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI Gene IDs: 10320, 22806); immunoglobulin superfamily member 11 (IGSF11; N NCBI Gene ID: 152404); indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI Gene ID: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI Gene ID: 3480, 3482); insulin-like growth factor (e.g., IGF1, IGF2; NCBI Gene ID: 347 9, 3481); insulin receptor (INSR, CD220; NCBI Gene ID: 3643); integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene ID: 3678, 3685, 3688, 3695, 3698); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI Gene ID: 3383); interleukin-1 receptor-associated kinase 4 (IRAK4; NCBI Gene ID: 51135); interleukin receptor receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI Gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8 (CXCL8), IL10 (TGIF), IL12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-; 29 (IFNL1); NCBI Gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618); isocitrate dehydrogenase (NADP()1) (e.g., IDH1, IDH2; NCBI Gene IDs: 3417, 3418); Janus kinases (e.g., JAK1, JAK2, JAK3; NCBI Gene IDs: 3417, 3418); NCBI Gene ID: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI Gene ID: 354); killer cell immunoglobulin-like receptors, Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KI R3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI Gene IDs: 3802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285; killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRR C4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914; kinase insert domain receptor (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1 ; NCBI Gene ID: 3814); KIT proto-oncogene, receptor tyrosine kinase (KIT, c-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene, GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene, Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4 035); leucine-rich repeat-containing 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI Gene ID: NCBI Gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI Gene ID: 27076); lymphocyte activation 3 (LAG3; CD223; NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene ID: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); lysyl oxidase (LOX; NCBI Gene ID: 4015); lysyl oxidase-like 2 (LOXL2; NCBI Gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI Gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136; NCBI Gene ID: 4486);MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: ID: 3105, 3133, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene ID: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MM P3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI Gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148 , 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI Gene ID: 4170); MDM2 oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI Gene ID: 2475); melan-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene ID: 4 157, 4148); MER proto-oncogene, tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN; NCBI Gene ID: 10232); MET proto-oncogene, receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC class I polypeptide-related sequences (e.g., MICA, MICB; NCBI Gene IDs: 4277, 100507436);Mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12; NCBI Gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2) ), NCBI Gene ID: 4217, 1326); mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene ID: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125; NCBI Gene IDs: 4582, 4586, 94025); MYC proto-oncogene, bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4082) NCBI Gene ID: 4883); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, a MAGE family member (NDN; NCBI Gene ID: 4692); nectin cell adhesion molecules (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4); NCBI Gene ID: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829);Neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI gene ID: 49; 14, 4915, 4916); NFKB-activating protein (NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); Nuclear factor coactivator PaB (NFKB1, NFKB2; NCBI Gene ID: 4790, 4791); nuclear factor, erythroid 2-like 2 (NFE2L2; NRF2; NCBI Gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI Gene ID: 3164); nucleolin (NCL; NCBI Gene ID: 4691); nucleophosmin 1 (NPM1; NCBI Gene ID: 4869); nucleotide-binding oligomerization domain-containing 2 (NOD2; NCBI Gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI Gene ID: 64127); NCBI Gene ID: 4521); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI Gene ID: 4255); Opioid receptor delta 1 (OPRD1; NCBI Gene ID: 4985); Ornithine decarboxylase 1 (ODC1; NCBI Gene ID: 4953); C=O glutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); Parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); Periostin (POSTN; NCBI Gene ID: 4967); NCBI Gene ID: 10631); peroxisome proliferator-activated receptors (e.g., PPARA (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene ID: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA (PI3K alpha), PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma);NCBI Gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3 ; NCBI Gene ID: 5292, 11040, 415116); placental growth factor (PGF); NCBI Gene ID: 5228); plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene ID: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (poliovirus receptor, PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); polo-like kinase 1 (PLK1; NCBI Gene ID: 5347); poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); polycomb protein EED (EED; NCBI Gene ID: 8726); porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcription regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL; NCBI Gene ID: 6490); progesterone receptor (progesterone receptor, PGR; NCBI Gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI Gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI Gene ID: 80380); Prominin1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (P; ML; NCBI Gene ID: 5371); propiosin (PSAP; NCBI Gene ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene IDs: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI gene ID: 5698); protein arginine methyltransferases (e.g., PRMT1, PRMT5; NCBI gene IDs: 3276, 10419); protein kinase N3 (PKN3; NCBI gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI gene ID: 5754); protein tyrosine phosphatase receptor (PTPRB (PTPB), PTP RC (CD45R); NCBI Gene ID: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene, serine / threonine kinase (RAF1, c-Raf; NCBI Gene ID: 79037) I Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); Ras homolog family member C (RHOC; NCBI Gene ID: 389); Ras homolog, mTORC1-binding (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine / threonine protein kinase 1 (RIPK1; NCBI Gene ID: 8737); ret proto-oncogene (RET; NCBI Gene ID: 5979); retinoic acid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091);Retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene ID: 5914, 5916); retinoid X receptor (e.g., RXRA, RXRB, RXRG; NCBI Gene ID: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinase (e.g., ROCK1, ROCK2; NCBI Gene ID: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-beta1; NCBI Gene ID: 6198); ring finger protein 128 (RNF128, G RAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1, receptor tyrosine kinase (ROS1; NCBI Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium-binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted flutrient-related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6423) NCBI Gene ID: 6696); secretoglobin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene ID: 6401, 6402, 6403); semaphorin 4D (semaphorin, SEMA4D; CD100; NCBI Gene ID: 10507); sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI Gene ID: 27036, 2 7180, 89790); signal regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); signal transducer and activator of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene ID: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; NCBI Gene ID: 23410); signaling lymphocyte activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF; 7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI Gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); smooth, frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (EPHX2; NCBI Gene ID: 2053); solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34) A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI Gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI Gene IDs: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecule (SHH; NCBI Gene ID: 6469); Sp1 transcription factor (SP1; NCBI Gene ID: 6667); sphingosine kinase (e.g., , SPHK1, SPHK2; NCBI Gene ID: 8877, 56848); sphingosine-1-phosphate receptor 1 agonist (S1PR1, CD363; NCBI Gene ID: 1901); spleen-related tyrosine kinase (SYK; NCBI Gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI Gene ID: 23451); SRC proto-oncogene, non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family members member 1 (STEAP1; NCBI Gene ID: 26872); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interactor 1 (STING1; NCBI Gene ID: 340061); superoxide dismutase 1 (SOD1, ALS1; NCBI Gene ID: 6647); suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI Gene IDs: 8651, 9021); synapsin 3 (SYN3; NCBI Gene ID: 8224);Syndecan 1 (SDC1, CD138, syndecan; NCBI Gene ID: 6382); synuclein alpha (SNCA, PARK1; NCBI Gene ID: 6622); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene ID: 1 D:6869, 6870); TANK-binding kinase 1 (TBK1; NCBI Gene ID: 29110); tankyrase (TNKS; NCBI Gene ID: 8658); TATA box-binding protein-associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25 976); lymphocyte-specific protein tyrosine kinase (TEC); NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); human telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371); 3 prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombopoiesis Modulin (THBD, CD141; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene ID: 7606, 7608); thyrotropin receptor (TSHR; NCBI Gene ID: 7253);TNF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), T; NFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL); NCBI Gene IDs: 944, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD 286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793; transferrin (TF; NCBI Gene ID: 7018); transferrin receptor (TFRC, CD71; NCBI Gene ID: 7037); transforming growth factors (e.g., TGFA, TGFB1; NCBI Gene IDs: 7039, 7040); transforming growth factor receptors (e.g., TG FBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 7049); transforming protein E7 (E7; NCBI Gene ID: 1489079); transglutaminase 5 (TGM5; NCBI Gene ID: 9333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); trigger receptor expressed in myeloid cells cytoplasmic endothelial cells (e.g., TREM1 (CD354), TREM2; NCBI Gene ID: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162); tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); tryptophan hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1;NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (C; T NFRSF10D, TNFRSF11A, TNFRSF11B(OPG), TNFRSF12A, TNFRSF13B, TNFR13C(, CD268, BAFFR), TNFRSF14(CD270, LIGH TR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI gene ID: 355 , 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27 242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2, mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7299); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); immunoglobulin-like and EGF-like domain 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine protein phosphatase, non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme E2I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI Gene ID: 513 77); ubiquitin-specific peptidase 7 (USP7; NCBI Gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16-binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing protein (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI Gene IDs: 7422, 7423); vimentin (VIM; NCBI Gene ID: 7431); vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7-H4; NCBI Gene ID: 79679 ); V-set immunoregulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRNRecQ-like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain-containing transcription factor 1 (WWTR1; TAZ; NCBI Gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375); XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI Gene ID: 2829); Yes1-associated transcription factor (YAP1; NCBI Gene ID: 10413); zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535).

[0075] In some embodiments, the one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Adenosine A receptor (ADORA2A; NCBI gene ID: 135) 2Breceptor (ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase α (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); Fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin-associated protein (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI Gene ID: 3845; including mutations such as KRAS G12C or G12D; mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death-ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 29126) Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); signal-regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209);tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, CD134, OX40; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily, member 9 (TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily, member 18 (TNFRSF18, CD357, GITR; NCBI Gene ID: 8784); WRNRecQ-like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807); and others. Exemplary Mechanisms of Action Immune Checkpoint Modulators

[0076] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor environment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate NK cell responses (e.g., as reviewed in Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition of regulatory T cells (Tregs) or Treg depletion can relieve their suppression of anti-tumor immune responses and have anti-cancer effects (e.g., Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka, et al., J. Immunol. (2020) 4:459-77). and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0077] Examples of immune checkpoint proteins or receptors include CD27 (NCBI Gene ID: 939), CD70 (NCBI Gene ID: 970); CD40 (NCBI Gene ID: 958), CD40LG (NCBI Gene ID: 959); CD47 (NCBI Gene ID: 961), SIRPA (NCBI Gene ID: 140885); CD48 (SLAMF2; NCBI Gene ID: 962), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI Gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI Gene ID: 8832), CD96 (NCBI Gene ID: 10225), CD160 (NCBI Gene ID: 10226), and the like. NCBI Gene ID: 11126), MS4A1 (CD20; NCBI Gene ID: 931), CD244 (SLAMF4; NCBI Gene ID: 51744); CD276 (B7H3; NCBI Gene ID: 80381); V-set domain-containing T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI Gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI Gene ID: 11148); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI Gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI Gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4 , TRAILR1; NCBI Gene ID; 8797), TNFRSF9 (CD137; NCBI Gene ID; 3604), TNFSF9 (CD137L; NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270; NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA), N NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1 ; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI Gene ID: 5819); CD226 (DNAM-1; NCBI Gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, C D155; NCBI Gene ID: 5817); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); T-cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); T-cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4; NCBI Gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI Gene ID: 84868); Galectin 9 (LGALS9; NCBI Gene ID: 3965);Lymphocyte activation 3 (LAG3, CD223; NCBI Gene ID: 3902); signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI Gene ID: 6504); lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI Gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI Gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI Gene ID: 57823); UL16-binding protein 1 (ULBP1; NCBI Gene ID: 80329); UL16-binding protein 2 (ULBP2 ; NCBI Gene ID: 80328); UL16-binding protein 3 (ULBP3; NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154064); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1; NCBI Gene ID: 3811, e.g., lirilumab (IPH-21; 02, IPH-4102); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A; NCBI Gene ID: 3821); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI Gene ID: 22914); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI Gene ID: 3822); killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI Gene ID: 3823); killer cell lectin killer cell immunoglobulin-like receptor C4 (KLRC4, NKG2F; NCBI gene ID: 8302); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI gene ID: 3802); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI gene ID: 3803); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 3 (KIR2DL3; NCBI gene ID: 38 04); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1; NCBI gene ID: 3824); killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI gene ID: 10219); sialic acid-binding Ig-like lectin 7 (SIGLEC7; NCBI gene ID: 27036); and sialic acid-binding Ig-like lectin 9 (SIGLEC9; NCBI gene ID: 27180).

[0078] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PV RIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0079] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94), killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid-binding Ig-like lectin 7 (SIGLEC7); and sialic acid-binding Ig-like lectin 9 (SIGLEC9). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more agonists or activators of one or more NK cell-stimulatory immune checkpoint proteins or receptors. Exemplary NK cell-stimulatory immune checkpoint proteins or receptors include: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0080] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0081] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, and KN-04. 4, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0082] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, balvalumab, phenytoin ... Stirimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimuzumab (CBT-501), LZM-009, prorugolimab (BCD-100), rodapolimab (LY-3300054), SHR-1201, camrelizumab (S HR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dostallimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS -1001 (WBP-3155), embafolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, dimvelelimab (AB122), spartalizumab (P DR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1) RO- 7247669(PD-1 / LAG-3), MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD- 1 / TIM-3), RG7769(PD-1 / TIM-3), TAK-252(PD-1 / OX40L), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp alfa (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, PD-L1 inhibitors include CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0083] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vivostarob, domvanalimab, domvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0084] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0085] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate the suppression of anti-tumor immune responses and may have anti-cancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment.

[0086] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitors can suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitors can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitors can modulate cell phenotype and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include CCR4 (NCBI Gene ID: 1233) antagonists and degraders of Ikaros zinc finger proteins (e.g., Ikaros (IKZF1; NCBI Gene ID: 10320), Helios (IKZF2; NCBI Gene ID: 22807), Aiolos (IKZF3; NCBI Gene ID: 22806), and Eos (IKZF4; NCBI Gene ID: 64375).

[0087] Examples of heliolytic agents that may be co-administered include, but are not limited to: I-57 (Novartis), and compounds disclosed in WO 2019038717, WO 2020012334, WO 20200117759, and WO 2021101919.

[0088] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting antibody is an antibody-drug conjugate (ADC). Exemplary targets of Treg depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0089] In some embodiments, Treg inhibitors or Treg depletors that may be co-administered include C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic Treg receptor 4 (CCR4; CD184), TNFRSF18 (GITR, CD357), TNFRSF18 ... Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit and combinations thereof.

[0090] Examples of Treg-depleting anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in WO2021163064, WO2020138489, and WO2021152186.

[0091] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0092] Inhibition, depletion, or reprogramming of unstimulated myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550; WO 2016049641). Exemplary targets for depleting or reprogramming unstimulated myeloid cells include triggering receptors expressed on myeloid cells, TREM-1 (CD354, NCBI Gene ID: 54210) and TREM-2 (NCBI Gene ID: 54209). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more myeloid cell-depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; an antibody disclosed in WO 2019032624) or an anti-TREM-2 antibody (e.g., PY314; an antibody disclosed in WO 2019118513). Cluster of differentiation agonists or activators

[0093] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agent that targets a cluster of differentiation (CD) marker. Exemplary CD marker-targeting agents that may be co-administered include: A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, and pertuzumab (Perjeta). , pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402 / HL A-A0201 restricted epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranelgene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverenvatinib dimesylate (HQP-1351), cabozantinib, ponatinib , and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and International Publication Nos. 2016196388, 2016033570, 2015157386, 199203459, 199221766, 2004080462, 2005020921, 2006009755, and 200707803 4, International Publication No. 2007092403, International Publication No. 2007127317, International Publication No. 2008005877, International Publication No. 2012154480, International Publication No. 2014100620, International Publication No. 2014039714, International Publication No. 2015134536, International Publication No. 2017167182, International Publication No. 2018112136, International Publication No. 2018112140, International Publication No. 2019155067, International Publication No. 2020076105, International Application PCT No. US2019063091, International Publication No. 19173692, International Publication No. 2016179517, International Publication No. 2017096179, International Publication No. 2017096182, International Publication No. 2017096281, International Publication No. 2018089628, International Publication No. 2017096179, International Publication No. 2018089628, International Publication No. 2018195321, International Publication No. 2020014643, International Publication No. 2019160882, International Publication No. 2018195321, International Publication No. 200140307, ​​International Publication No. 2002092784, International Publication No. 2007133811, International Publication No. 2009046541,International Publication No. 2010083253, International Publication No. 2011076781, International Publication No. 201305, 6352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669, International Publication No. 2018107058, International Publication No. 2018190719, International Publication No. 2018210793, International Publication No. 2019023347, International Publication No. 2019042470, International Publication No. 2019175218, International Publication No. 2019183266, International Publication No. 2020013170, International Publication No. 2020068752, Cancer Disov. 2019 Jan 9(1):8; and Gariepy J., et al.106th Annu These include, but are not limited to, agents that target CD markers, such as the compounds disclosed in Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0094] In some embodiments, agents targeting CD markers that may be co-administered include the following: PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, lobritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117 - small molecule inhibitors such as ADC, AZD3229, telatinib, borolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), Plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0095] In some embodiments, agents targeting CD markers that may be co-administered include the following: interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly ICLC (NSC-301463), reboxone, apoxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, levothyroxine ... Small molecule agonists such as siquimod, sergantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, ritenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0096] In some embodiments, agents targeting CD markers that may be co-administered include the following: tafasitamab (MOR208; MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzalutamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, cericlerumab ( RG7876), APX-005M, ABBV-428, ABBV-927, mitazarimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (caviralitumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulukafusp alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulukafusp alfa (RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / Her 2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, leratolimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enselimab (TSR-033), atipotuzumab, Breva Rex (Mab-AR-20.5), MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006 , INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and antibodies such as compounds published in WO 2017 / 096179, WO 2017096276, WO 2017096189, and WO 2018089628.

[0097] In some embodiments, agents targeting CD markers that may be co-administered include the following: CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, l iso-cel, lysocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL-armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silent IL-6 expression, cancer, Shanghai Unicar Therapeutics Biopharmaceutical Therapeutics Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20 CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (CTL-019), anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma), MB-CART2019.1(CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132(CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NS. CLC), ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D LIGAND MODULATOR), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, or therapies disclosed in WO2012079000 or WO2017049166. Cluster of differentiation 47 (CD47) inhibitors

[0098] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621. Additional exemplary anti-CD47 antibodies include the following: CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188), lemzoparimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY -102, KD-015, ALX-148, AK-117, TTI-621, TTI-622, or International Publication No. 199727873, International Publication No. 199940940, International Publication No. 2002092784, International Publication No. 2005044857, International Publication No. 2009046541, International Publication No. 2010070047, International Publication No. 2011143624, International Publication No. 2012170250, International Publication No. 2013109752, International Publication No. 2013119714, International Publication No. 2014087248, International Publication No. 2015191861, International Publication No. 2016022971, International Publication No. 2016023040, International Publication No. 2016024021, International Publication No. 2016081423, International Publication No. 2016109415, International Publication No. 2016141328, International Publication No. 2016188449, International Publication No. 2017027422, International Publication No. 2017049251, International Publication No. 2017053423, International Publication No. 2017121771, International Publication No. 2017194634, International Publication No. 2017196793, International Publication No. 2017215585, International Publication No. 2018075857, International Publication No. 2018075960, International Publication No. 2018089508, International Publication No. 2018095428,International Publication No. 2018137705, International Publication No. 2018233575, International Publication No. 2019027903, International Publication No. 2019034895, International Publication No. 2019042119, International Publication No. 2019042285, International Publication No. 2019042470, International Publication No. 2019086573, International Publication No. 2019108733, International Publication No. 2019138367, International Publication No. 2019144895, International Publication No. 201 and WO 2020009725. In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is magrolimab.

[0099] In some embodiments, the CD47 inhibitor is IBI-322 (CD47 / PD-L1 ), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L 1), PT-217, (CD47 / DLL3), IMM-26011 (CD47 / FLT3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / H and bispecific antibodies targeting CD47, such as ER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801. SIRPα targeting agent

[0100] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with a SIRPα targeting agent (NCBI Gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents include SIRPα inhibitors (such as AL-008, RRx-001, and CTX-5861) and anti-SIRPα antibodies (such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPα / PD-L1). Additional SIRPα targeting agents of use are described in, for example, WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 201206627, WO 201306627, WO 20140307, ​​WO 20140307, ​​WO 20140308, WO 20140309 ... 13056352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669, International Publication No. 2018107058, International Publication No. 2018190719, International Publication No. 2018210793, International Publication No. 2019023347, International Publication No. 2019042470, International Publication No. 2019175218, International Publication No. 2019183266, International Publication No. 2020013170 and International Publication No. 2020068752. FLT3R agonists

[0101] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an FLT3R agonist. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with a FLT3 ligand. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with an FLT3L-Fc fusion protein, for example, as described in WO2020263830. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with GS-3583 or CDX-301. In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with GS-3583.

[0102] Agonists or activators of TNF Receptor Superfamily (TNFRSF) members. In some embodiments, the antibodies and / or fusion proteins provided herein inhibit one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355). , TNFRSF7 (CD27, NCBI gene ID; 939), TNFRSF8 (CD30, NCBI gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID; 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8796). TNFRSF11A (CD265, RANK, NCBI Gene ID; 8792), TNFRSF11B (NCBI Gene ID; 4982), TNFRSF12A (CD266, NCBI Gene ID; 51330), TNFRSF13B (CD267, NCBI Gene ID; 23495), TNFRSF13C (CD268, NCBI Gene ID; 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID; 115650), Gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBI Gene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

[0103] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tabolixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0104] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0105] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0106] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0107] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0108] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO 2017096179 and WO 2018089628.

[0109] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20). Bispecific T cell engager

[0110] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with a bispecific T cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), odronextamab (REGN-1979; CD20 / CD3). 3), MCLA-117(CD3 / CLEC12A), JNJ-0819(heme / CD3), JNJ-7564(CD3 / heme), AMG-757(DLL3-CD3), AMG-330(CD33 / CD3), AMG-420(BCMA / CD 3),AMG-427(FLT3 / CD3),AMG-562(CD19 / CD3),AMG-596(EGFRvIII / CD3),AMG-673(CD33 / CD3),AMG-701(BCMA / CD3),AMG-757(DLL3 / CD3 ), AMG-211 (CEA / CD3), blinatumomab (CD19 / CD3), huGD2-BsAb (CD3 / GD2), ERY974 (GPC3 / CD3), GEMoab (CD3 / PSCA), RG6026 (CD20 / CD3), RG61 94(HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw123), JNJ-9383(MGD-015), AMG-424(CD38 / CD3), tidutamab(XmAb-18087 (SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), tidutamab (XmAb-18087; SSTR2 / CD3), catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828;Examples of suitable anti-CD3 binding bispecific molecules include CD20 / CD3, CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc. Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230). Bispecific and trispecific natural killer (NK) cell engagement Ja

[0111] In some embodiments, the antibodies and / or fusion proteins provided herein are bi-specific NK-cell engagers (BiKEs) or Tri-specific NK-cell engager (TriKE) (e.g., without Fc), or NK cell activating receptors, e.g., CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7 ... The co-administration is typically performed with bispecific antibodies (e.g., with Fc) against killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE, that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54. MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0112] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of the MCL1 apoptosis regulator, a BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI Gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO2018183418, WO2016033486, and WO2017147410. SHP2 inhibitors

[0113] In some embodiments, antibodies and / or fusion proteins provided herein are administered with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI Gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO2018172984 and WO2017211303. Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders

[0114] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184).

[0013] Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300. Apoptosis signal-regulating kinase (ASK) inhibitors

[0115] In some embodiments, the antibodies and / or fusion proteins provided herein are directed to ASK inhibitors, such as mitogen-activated protein kinase kinase kinase 5 (MKI). AP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO2013112741 (Gilead Sciences). Bruton's tyrosine kinase (BTK) inhibitors

[0116] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315. Cyclin-dependent kinase (CDK) inhibitors

[0117] In some embodiments, the antibodies and / or fusion proteins provided herein are directed to cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); Gene ID: 1019); cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID: 1021); cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID: 1022), or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02. Discoidin domain receptor (DDR) inhibitors

[0118] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication Nos. 2009-0142345 (Takeda Pharmaceutical), 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations). Targeted E3 ligase ligand conjugates

[0119] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in conjunction with a target E3 ligase-ligand conjugate. Such conjugates comprise a target protein-binding moiety and an E3 ligase-binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAA)). P1, c-IAP2, NIL-IAP, Bruce, and survival E3 ubiquitin ligase binding site, Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding site, and cereblon E3 ubiquitin ligase binding site minute, mouse double minute 2 homolog (MDM2) E3 The targeting E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein described herein and an E3 ligase ligand or binding moiety. In some embodiments, the targeting E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein selected from Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091). In some embodiments, the targeting E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., International Publication No. WO 2018098280. In some embodiments, the targeting E3 ligase ligand conjugate comprises an interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); a rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD protein; and a binding moiety that targets or binds to the E3 ligase ligand or binding moiety. See, e.g., International Publication Nos. WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, and WO 2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, for example, in WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649. Histone deacetylase (HDAC) inhibitors

[0120] In some embodiments, the antibodies and / or fusion proteins provided herein are further combined with an inhibitor of a histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat. Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0121] In some embodiments, the antibodies and / or fusion proteins provided herein are combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, Epaca These include ridostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus kinase (JAK) inhibitors

[0122] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. Lysyl oxidase-like protein (LOXL) inhibitors

[0123] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of a LOXL protein, e.g., LOXL1 (NCBI Gene ID: 4016), LOXL2 (NCBI Gene ID: 4017), LOXL3 (NCBI Gene ID: 84695), LOXL4 (NCBI Gene ID: 84171), and / or LOX (NCBI Gene ID: 4015). Examples of LOXL2 inhibitors include the antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2011 / 097513 (Gilead Biologics). Matrix metalloproteinase (MMP) inhibitors

[0124] In some embodiments, the antibodies and / or fusion proteins provided herein are directed against a matrix metallopeptidase (MMP), such as MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP18 (NCBI Gene ID: 4327), MMP19 (NCBI Gene ID: 4330), MMP20 (NCBI Gene ID: 4331), MMP21 (NCBI Gene ID: 4332), MMP22 (NCBI Gene ID: 4333), MMP23 (NCBI Gene ID: 4334), MMP24 (NCBI Gene ID: 4335), MMP25 (NCBI Gene ID: 4336), MMP26 (NCBI Gene ID: 4337), MMP27 (NCBI Gene ID: 4338), MMP28 (NCBI Gene ID: 4339), MMP29 (NCBI Gene ID: 4340), MMP29 (NCBI Gene ID: 4341), MMP29 (NCBI Gene ID: 4342), MMP29 (NCBI Gene ID: 4343), MMP29 (NCBI Gene ID: 4344), MMP29 (NCBI Gene and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0125] In some embodiments, the antibodies and / or fusion proteins provided herein are directed against the KRAS proto-oncogene, GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); the NRAS proto-oncogene, GTPase (NRAS; also known as NS6 ;CMNS;NCMS;ALPS4;N-ras;NRAS1;NCBI Gene ID:4893) or HRAS proto-oncogene, an inhibitor of a GTPase (HRAS; also known as CTLO;KRAS;HAMSV;HRAS1;KRAS2;RASH1;RASK2;Ki-Ras;p21ras;CH-RAS;cK-ras;H-RASIDX;c-Ki-ras;C-BAS / HAS;C-HA-RAS1;NCBI Gene ID:3265). Ras inhibitors can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that may be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1(G12C), adagrasib (MRTX-849), ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849(G12C), and K-Ras(G12D) selective inhibitory peptides (including KRpep-2 and KRpep-2d). Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adaptor-, AZD-4785, siG12D-LODER™, and siG12D-exosomes.Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, rabocertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include lidigosertib. Exemplary PI3K inhibitors that may be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Exemplary AKT inhibitors that may be co-administered include capivasertib and GSK2141795. Exemplary PI3K / mTOR inhibitors that may be co-administered include daptolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, cancer), racemetyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Also, K-RAS and mutant N-RAS can be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Mitogen-activated protein kinase (MEK) inhibitors

[0126] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0127] In some embodiments, the antibodies and / or fusion proteins provided herein are directed to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, and / or an inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110δ, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, and copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7 604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication No. 2005 / 113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Sciences, Inc., New York, NY, USA) Calistoga), WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga), and WO 2014 / 201409 (Gilead Sciences). Spleen Tyrosine Kinase (SYK) inhibitor

[0128] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI gene ID: 6850). An example of a SYK inhibitor is 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine. , BAY-61-3606, celdulatinib (PRT-062607), entpretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002) and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut), and those described in U.S. Patent Application Publication No. 20150175616. Toll-like receptor (TLR) agonists

[0129] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793). Examples of TLR7 agonists that may be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod analogs, and the like. analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences). Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014056953 (Janssen), WO 2014076221 (Janssen), WO 2014128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that may be co-administered is NKTR-262.Examples of TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 2014007 3642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (. Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 2013 / 0251673 (Novira Therapeutics). Exemplary TLR9 agonists that may be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Tyrosine kinase inhibitors (TKIs)

[0130] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with a tyrosine kinase inhibitor (TKI), which can target the epidermal growth factor receptor (EGFR) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, and KX2-391 (Src ), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib, L-malic acid, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeted agents include neratinib, tucatinib (ONT-380), tecevatinib, mobocertinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib (LECLAZA®, and Booth, et al., Cancer Biol Ther. 2018 Feb. 1;19(2):132-137. Antibodies that target EGFR include, but are not limited to, modotuximab, cetuximab sarotarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab. chemotherapy drugs

[0131] In some embodiments, the antibodies and / or fusion proteins provided herein are The drug is administered in conjunction with a chemotherapy or anti-neoplastic agent.

[0132] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethyleneimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptoxanthin; ficins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi I1), dynemycins, including dynemycin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin , detorubicin, 6-diazo-5-C=OL-norleucine, doC=O rubicin (including morpholino-C=O rubicin, cyanomorpholino-C=O rubicin, 2-pyrrolino-C=O rubicin, and deoxy-C=O rubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodolubicin, streptonigrin, streptozocin, tubercidin, ube antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as furoic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, veracrine A, roridin A, and anguidine; taxoids, such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel;Sabizablin (Veru-111); platinum analogues, such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestravcil; bisantrene; edatrexate; defofamine; demecolcine; di; Aziquone; Elformutine; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Leucovorin; Lonidamine; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Fluoropyrimidines; Folinic acid; Podophyllic acid, 2-ethylhydrazide; Procarbazine; Polysaccharide K (PSK); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2''-Trichlorotriemyl azathioprine amine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin, aminopterin, xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), as well as pharmaceutically acceptable salts, acids, or derivatives of any of the above. Such agents can be conjugated to antibodies or any of the targeting agents described herein to create antibody drug conjugates (ADCs) or targeted drug conjugates. Antihormonal drugs

[0133] Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0134] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0135] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0136] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (apatorsen).

[0137] Examples of progesterone receptor antagonists include onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri -Cyclen) and levonorgestrel. Antiangiogenic agents

[0138] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-angiogenic agent. Anti-angiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necapranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shell), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,l-3,4-dehydroproline, thiaproline, and the like. benzodiazepine, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinases-3 (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate, d-penicillamine, β-1 anticollagenase serum, alpha-2 antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthonylate disodium or "CCA", thalidomide, angiogenesis-suppressing steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be co-administered include bevacizumab, vanucizumab, faricimab, zilpacimab (ABT-165; DLL4 / VEGF), or nabicikizumab (OMP-305B83; DLL4 / VEGF). antifibrotic agents

[0139] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an anti-fibrotic agent. Anti-fibrotic agents that may be co-administered include compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Patent No. 4,965,288, which relates to inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal collagen deposition, and U.S. Patent No. 4,997,854, which relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, each of which is incorporated herein by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, U.S. Pat. No. 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application No. 20040248871, which are incorporated herein by reference.

[0140] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that generate resonance-stabilized products after binding to the carbonyl, such as the following primary amines: ethylenamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; and unsaturated or saturated haloamines. , for example, 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamines; and selenohomocysteine ​​lactone.

[0141] Other antifibrotic agents are copper chelators, which may or may not be cell-permeable. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate. anti-inflammatory agents

[0142] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with an anti-inflammatory agent. Exemplary anti-inflammatory agents include arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 377678), and the like. NCBI Gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0143] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that can be co-administered include mofezolac, GLY-230, and TRK-700.

[0144] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743) that may be co-administered include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Dual COX-2 / carbonic anhydrase inhibitors that may be co-administered include HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of CA inhibitors include pormacoxib and imrecoxib.

[0145] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that can be co-administered include LY3023703, GRC27864, and the compounds disclosed in WO 2015 / 158204, WO 2013 / 024898, WO 2006 / 063466, WO 2007 / 059610, WO 2007 / 124589, WO 2010 / 100 249, WO 2010 / 034796, WO 2010 / 034797, WO 2012 / 022793, WO 2012 / 076673, WO 2012 / 076672, WO 2010 / 034798, WO 2010 / 034799, WO 2012 / 022792, WO 2009 / 103778, WO 2011 / 048004, WO 201 2 / 087771, WO 2012 / 161965, WO 2013 / 118071, WO 2013 / 072825, WO 2014 / 167444, WO 2009 / 138376, WO 2011 / 023812, WO 2012 / 110860, WO 2013 / 153535, WO 2009 / 130242, WO 2009 / 146696, WO Examples of compounds that can be co-administered include those described in International Publication Nos. 2013 / 186692, 2015 / 059618, 2016 / 069376, 2016 / 069374, 2009 / 117985, 2009 / 064250, 2009 / 064251, 2009 / 082347, 2009 / 117987, and 2008 / 071173. Additionally, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0146] Carbonic anhydrases that may be co-administered (e.g., CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA Examples of inhibitors of one or more of CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632) include acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0147] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include meclofenamate sodium and zileuton.

[0148] Soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) inhibitors that may be co-administered include those described in WO 2015 / 148954. Dual COX-2 / SEH inhibitors that may be co-administered include those described in WO 2012 / 082647. Dual SEH and fatty acid amide hydrolase inhibitors (FAAH; NCBI Gene ID: 2166) that may be co-administered. Examples of such compounds include those described in WO 2017 / 160861.

[0149] Examples of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) molecules that can be co-administered include GS-4875, GS-5290, BHM-078, and the therapeutic agents described in WO 2006 / 124944, WO 2006 / 124692, WO 2014 / 064215, WO 2018 / 005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4): 558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9): 1015-35; Wu, et al., Bioorg Med Chem Lett. (2009) 19(13): 3485-8; Kaila, et al., Bioorg Med Chem. (2007) 15(19): 6425-42; and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16): 4758-61. Tumor oxygenators

[0150] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that can be co-administered include, for example, hypoxia-inducible factor-1α (HIF-1α) inhibitors, such as PT-2977 and PT-2385; VEGF inhibitors, such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding protein (HNOX)), such as OMX-302 and HNOX proteins, as described in International Publication Nos. 2007137767, 2007139791, 2014107171, and 2016149562. immunotherapy agents

[0151] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an antibody. Examples of immunotherapeutic agents that may be co-administered include abagovomab, AB308, ABP-980, adecatumumab, afutumumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitunomab, atezolizumab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumab, brentuximab, camidanlumab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivastatin, and rivaroxaban. Tuzumab, conatumumab, dacetuzumab, darotuzumab, daratumumab, detumomab, dinutuximab, dombanalimab, drozitumab, durigotumab, dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab, framvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glenbatumumab, ibuprofen, Britumomab, igovomab, imgatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minletumomab, mitumomab, mogamulitumab, moxetumomab, naptumomab, narutuzumab Mab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, palsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radletuzumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, Rituximab can be used to treat indolent B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy is particularly effective.

[0152] The exemplified therapeutic antibodies may be further labeled with or combined with radioisotope particles such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0153] In some embodiments, the immunotherapeutic agent is an antibody drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein.Examples of ADCs that may be co-administered include gemtuzumab, brentuximab, belantamab (e.g., belantamab mafodotin), camidanlumab (e.g., camidanlumab tesirin), trastuzumab (e.g., trastuzumab deruxtecan; trastuzumab emtansine), inotuzumab, glembatumumab, anetumab, mirvetuximab (e.g., mirvetuximab sovatansine), depatuximab, vadasotuximab, labetuzumab, lazilatuzumab (e.g., lazilatuzumab vedotin), Roncatuximab (e.g., roncatuximab tesulin), sacituzumab (e.g., sacituzumab govitecan), datopotomab (e.g., datopotomab deruxtecan; DS-1062; Dato-DXd), patrituzumab (e.g., patrituzumab deruxtecan), rifastuzumab, indosatumab, polatuzumab (e.g., polatuzumab vedotin), pinatuzumab, coltuximab, upifitamab (e.g., upifitamab rilsodotin), indituximab, milatuzumab, robalbutuzumab (e.g., robalbutuzumab mabutesillin), enfortumab (e.g., enfortumab vedotin), tisotumab (e.g., tisotumab vedotin), tusamitamab (e.g., tusamitamavutansine), dicitamab (e.g., dicitamab vedotin), terizotuzumab vedotin (ABBV-399), AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-9343, GSK2857916, Humax-TF-ADC, IMGN289, IMGN151, IMG Examples include N529, IMGN632, IMGN853, IMGC936, LOP628, PCA062, MDX-1203 (BMS936561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, SYD985, DS-7300, XMT-1660, IMMU-130, and IMMU-140.ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0154] Exemplary therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicin, ansamitocin, maytansine or analogs thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., doC=O rubicin, daunorubicin, epirubicin, idarubicin). , pyrrolobenzodiazepine (PBD) DNA crosslinker SC-DR002 (D6.5), duocarmycins, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepine (PBD) or dimers thereof, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), and other anti-cancer or anti-neoplastic agents described herein. In some embodiments, the therapeutic agent conjugated to the drug-conjugated antibody is a topoisomerase I inhibitor (e.g., a camptothecin analog such as irinotecan or its active metabolite SN38). In some embodiments, the therapeutic agent (e.g., an anti-cancer or anti-neoplastic agent) that can be conjugated to the drug-conjugated antibody, fragment thereof, or antibody mimetic comprises an immune checkpoint inhibitor. In some embodiments, the conjugated immune checkpoint inhibitor is a conjugated small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1), or CTLA4. In some embodiments, the conjugated small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the conjugated small molecule inhibitor of CTLA4 comprises BPI-002.

[0155] In some embodiments, an ADC that can be co-administered comprises an antibody targeting tumor-associated calcium signaling factor 2 (TROP-2; TACSTD2; EGP-1; NCBI gene ID: 4070). Exemplary anti-TROP-2 antibodies include TROP-2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Shanghai DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP-2-TRACTr (Janux Therapeutics), LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius) BioTech), LIV-2008b (Shanghai / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison), anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), KD-065 (Nanjing KAEDI Biotech), as well as International Publication No. 2020016662 (Abmart), International Publication No. 2020249063 (Bio-Thera Solutions), U.S. Patent Application Publication No. 20190048095 (Bio-Thera Solutions), U.S. Patent Application Publication No. 2013077458 (LivTech / Chiome), European Patent Application Publication No. 20110783675 (Chiome), International Publication No. 2015098099 (Daiichi Sankyo), International Publication No. 2017002776 (Daiichi Sankyo), International Publication No. 20201301 No. 25 (Daiichi Sankyo), International Publication No. 2020240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021093730 (Daiichi Sankyo), U.S. Patent Application Publication No. 9850312 (Daiichi Sankyo), Chinese Patent No. 112321715 (Biosion), U.S. Patent Application Publication No. 2006193865 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2011068845 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2016296633 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017021017 (Immunomedics / Gilead), U.S. Patent Application Publication No. 20172095 94 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2017274093 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018110772 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018185351 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018271992 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2018217227 (Immunomedics / Gilead) nomedics / Gilead), U.S. Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021093730 (Immunomedics / Gilead), U.S. Patent Application Publication No. 2021069343 (Immunomedics / Gilead), U.S. Patent No. 8435539 (Immunomedics / Gilead), U.S. Patent Patent No. 8435529 (Immunomedics / Gilead), U.S. Patent No. 9492566 (Immunomedics / Gilead), International Publication No. 2003074566 (Gilead), International Publication No. 2020257648 (Gilead), International Publication No. 2013039861 (Gilead), International Publication No. 2014163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (AbruzzoTheranostic / Oncoxx), International Publication No. 2018036428 (Sichuan Kelun Examples of antibodies include, but are not limited to, those described in Pharma, WO 2013068946 (Pfizer), WO 2007095749 (Roche), and WO 2020094670 (SynAffix). In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Pat. Nos. 7,238,785, 7,517,964, and 8,084,583, which are incorporated herein by reference. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anti-cancer agent joined by a linker. In some embodiments, the linker includes a linker disclosed in U.S. Pat. No. 7,999,083. In some embodiments, the linker is CL2A. In some embodiments, the drug moiety of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doC=O rubicin (dC=Orubicin, DOX), epirubicin, morpholino doC=O rubicin (morpholino-DOX), cyanomorpholino doC=O rubicin (cyanomorpholino-DOX), 2-pyrrolino-dC=O rubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, lutotecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanmycin, ansamycin, and epothilone. In some embodiments, the chemotherapeutic moiety is SN-38. In some embodiments, the antibodies and / or fusion proteins provided herein are administered with sacituzumab govitecan.

[0156] In some embodiments, ADCs that may be co-administered include antibodies targeting carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1; CD66a; NCBI gene ID: 634). In some embodiments, the CEACAM1 antibody is a CEACAM1 antibody (e.g., as described in International Publication No. WO 2005 / 024994). In some embodiments, the CEACAM1-ADC is hMN-14 (described in International Publication No. WO 2010093395) (anti-CEACAM-1-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are administered with CEACAM1-ADC IMMU-130.

[0157] In some embodiments, an ADC that may be co-administered comprises an antibody that targets an MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO 2006094192). In some embodiments, the HLA-DR-ADC is as described in WO 2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, antibodies and / or fusion proteins provided herein are administered with HLA-DR-ADC IMMU-140. Cancer Gene Therapy and Cell Therapy

[0158] In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include inserting normal genes into cancer cells to replace mutated or altered genes; genetic modification to silence mutated genes; genetic approaches to directly kill cancer cells; for example, infusion of immune cells designed to enhance the immune response to cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to replace most of the patient's own immune system to detect and kill cancer cells; genetic approaches to modify cell activity to further change the endogenous immune responsiveness to cancer. cell therapy

[0159] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more cell therapies. Exemplary cell therapies include the co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor-infiltrating lymphocytes (TIL), and / or dendritic cells (DC). Examples of cell therapy include, but are not limited to, T cell therapy, e.g., co-administration of a population of α / β TCR T cells, γ / δ TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, cell therapy involves co-administration of NK cell therapy, e.g., NK-92 cells. Optionally, cell therapy can involve co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0160] In some embodiments, cell therapy involves co-administering cells comprising a chimeric antigen receptor (CAR). In such therapy, a population of immune effector cells is engineered to express a CAR, where the CAR comprises a tumor antigen-binding domain. In T cell therapy, T cell receptors (TCRs) are engineered to target tumor-derived peptides displayed on the surface of tumor cells.

[0161] Regarding the structure of the CAR, in some embodiments, the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain is selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and D The signal transduction functional domains of one or more proteins selected from the group consisting of AP12.

[0162] In some embodiments, the costimulatory domain is selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD 4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 912), and CD1E (NCBI gene ID: 913). 12), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL 1. It comprises a functional domain of one or more proteins selected from the group consisting of CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0163] In some embodiments, the transmembrane domain is selected from the group consisting of the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E , ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0164] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapeutic agent (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof, or antibody mimetic) described herein binds to a tumor-associated antigen (TAA). In some embodiments, the tumor-associated antigen is one of the following: CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also known as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNe uSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer; TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate Stem cell antigen (PSCA); protease serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-β); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine protein kinase, ERBB2 (Her2 / neu); mucin 1, cell surface binding (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); protease prostatic acid phosphatase (PAP); elongation factor 2 mutant (ELF2M); ephrin B2; fibroblast activation protein α (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome (prosome, macropein) subunit, beta, 9 (LMP2); glycoprotein 100 (gp100); an oncogene fusion protein consisting of the breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (abl) (bcr-abl). Synthetic protein; tyrosinase; ephrin type A receptor 2 (EphA2); fucosyl-GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigen of prostate I (STEAP1); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR);G protein-coupled receptor class C group 5 member D (GPRCSD); X chromosome open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor β3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCRγ alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (P CTA-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc avian myeloma viral oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding factor (zinc finger protein)-like (sibling of BORIS or regulator of imprinted sites), squamous cell carcinoma antigen 3 recognized by T cells (SART3);Paired box tan; Protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A-kinase anchoring protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of an MHC-presented tumor-associated antigen.

[0165] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic factors, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA) ), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0166] In some embodiments, the antigen binding domain binds to an epitope of a target antigen or tumor-associated antigen (TAA) presented on a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer-testis antigen. In some embodiments, the cancer-testis antigen is acrosin-binding protein (ACRBP; CT23, OY-TES-1, SP32; NCBI Gene ID: 84519), alpha-fetoprotein (AFP; AFPD, FETA, HPAFP; NCBI Gene ID: 174), or the like. A-kinase anchor protein 4 (AKAP4; AKAP82, AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p82; NCBI Gene ID: 8852), ATPase family AAA domain containing 2 (ATAD2; ANCCA, CT137, PRO2000; NCBI Gene ID: 29028), kinetochore scaffold 1 (KNL1; AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1, hSpc105; NCBI Gene ID: 57082), centrosomal protein 55 (CEP55; C10orf3, CT111, MARCH, URCC6; NCBI Gene ID: 57082), I gene ID:55165), cancer / testis antigen 1A (CTAG1A;ESO1;CT6.1;LAGE-2;LAGE2A;NY-ESO-1;NCBI gene ID:246100), cancer / testis antigen 1B (CTAG1B;CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1;NC BI gene ID: 1485), cancer / testis antigen 2 (CTAG2; CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B; NCBI gene ID: 30848), CCCTC binding factor-like (CTCFL; BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2; NCBI Gene ID: 140690), catenin alpha 2 (CTNNA2; CAP-R, CAPR, CDCBM9, CT114, CTNR; NCBI Gene ID: 1496), cancer / testis antigen 83 (CT83; CXorf61, KK-LC-1, KKLC1; NCBI Gene ID: 203413), cyclin A1 (CCNA1; CT146; NCBI Gene ID: 8900), and DEAD-box helicase 43 (DDX43; CT13, HAGE; NCBI Gene ID: 55510). , developmental pluripotency associated 2 (DPPA2; CT100, ECAT15-2, PESCRG1; NCBI Gene ID: 151871), fetal and adult testicular expressed 1 (FATE1; CT43, FATE; NCBI Gene ID: 89885), FMR1 adjacent (FMR1NB; CT37, NY-SAR-35, NYSAR35; NCBI Gene ID: 158521), HORMA domain containing 1 (HORMAD1; CT46, NOHMA; NCBI Gene ID: 84072), insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3; CT98, IMP-3, IMP3, KOC, KOC1, VICKZ3; NCBI gene ID: 10643), leucine zipper protein 4 (LUZP4; CT-28, CT-8, CT28, HOM-TES-85; NCBI gene ID: 51213), lymphocyte antigen 6 family member K (LY6K; CT97, HSJ001348, URLC10, ly-6K; NCBI gene ID: 54742), maelstrom spermatogenesis transposon silencer (MAEL; CT128, SPATA35 ; NCBI Gene ID: 84944), MAGE family member A1 (MAGEA1; CT1.1, MAGE1; NCBI Gene ID: 4100); MAGE family member A3 (MAGEA3; CT1.3, HIP8, HYPD, MAGE3, MAGEA6; NCBI Gene ID: 4102); MAGE family member A4 (MAGEA4; CT1.4, MAGE-41, MAGE-X2, MAGE4, ​​MAGE4A, MAGE4B; NCBI Gene ID: 4103); MAGE family member A11 (MAGEA11; CT1.11, MAGE-11, MAGE11, MAGEA-11; NCBI Gene ID: 4110); MAGE family member C1 (MAGEC1; CT7, CT7.1; NCBI Gene ID: 9947); MAGE family member C2 (MAGEC2; CT10, HCA587, MAGEE1; NCBI Gene ID: 51438); MAGE family member D1 (MAGED1; DLXIN-1, NRAGE; NCBI Gene ID: 9500); MAGE family member D2 (MAGED2; 11B6, BARTS5, BCG-1, BCG1, HCA10, MAGE-D2; NCBI Gene ID: 10916), kinesin family member 20B (KIF20B; CT90, KRMP1, MPHOSPH1, MPP-1, MPP1; NCBI Gene ID: 9585), NUF2 component of the NDC80 kinetochore complex (NUF2; CDCA1, CT106, NUF2R; NCBI Gene ID: 83540), nuclear export factor 2 (NXF2; CT39, TAPL-2, TCP11X2; NCBI Gene ID: 56001), PAS domain-containing repressor 1 (PASD1; C. T63, CT64, OXTES1; NCBI Gene ID: 139135), PDZ-binding kinase (PBK; CT84, HEL164, Nori-3, SPK, TOPK; NCBI Gene ID: 55872), piwi-like RNA-mediated gene silencing 2 (PIWIL2; CT80, HILI, PIWIL1L, mili; NCBI Gene ID: 55124), melanoma preferentially expressed antigen (PRAME; CT130, M APE, OIP-4, OIP4; NCBI gene ID: 23532), sperm-associated antigen 9 (SPAG9; CT89, HLC-6, HLC4, HLC6, JIP-4, JIP4, JLP, PHET, PIG6; NCBI gene ID: 9043), nuclear X-linked family member A1-related sperm protein (SPANXA1; CT11.1, CT11.3, NAP-X, SPAN-X, SPAN-Xa, SPAN-Xb, SPA NX, SPANX-A; NCBI gene ID: 30014), SPANX family member A2 (SPANXA2; CT11.1, CT11.3, SPANX, SPANX-A, SPANX-C, SPANXA, SPANXC; NCBI gene ID: 728712), SPANX family member C (SPANXC; CT11.3, CTp11, SPANX-C, SPANX-E, SPANXE; NCBI gene ID: 64663), SPANX family member D (SPANXD; CT11.3, CT11.4, SPANX-C, SPANX-D, SPANX-E, SPANXC, SPANXE, dJ171K16.1; NCBI gene ID: 64648), SSX family member 1 (SSX1; CT5.1, SSRC; NCBI gene ID: 6756), SSX family member 2 (SSX2; CT5.2, CT5.2A, HD21, HOM-MEL-40, SSX; NCBI gene ID: 6757), synaptonemal structural protein 3 (SYCP3; COR1, RPRGL4, SCP3, SPGF4; NCBI gene ID: 50511), testis-expressed 14 intercellular bridge forming factor (TEX14; CT113, SPGF23; NCBI gene ID: 56155), transcription factor Dp family member 3 (TFDP3; CT30, DP4, HCA661; NCBI gene ID: 56156). 1 Gene ID: 51270), serine protease 50 (PRSS50; CT20, TSP50; NCBI Gene ID: 29122), TTK protein kinase (TTK; CT96, ESK, MPH1, MPS1, MPS1L1, PYT; NCBI Gene ID: 7272), and zinc finger protein 165 (ZNF165; CT53, LD65, ZSCAN7; NCBI Gene ID: 7718). T cell receptors (TCRs) and TCR-like antibodies that bind to epitopes of cancer-testis antigens presented on major histocompatibility complex (MHC) molecules are known in the art and can be used in the heterodimers described herein. Cancer-testis antigens associated with neoplasms are summarized, for example, in Gibbs, et al., Trends Cancer 2018 Oct;4(10):701-712, and in the CT database website at cta.lncc.br / index.php. Exemplary TCR and TCR-like antibodies that bind to MHC-presented epitopes of NY-ESO-1 are described, for example, in Stewart-Jones, et al., Proc Natl Acad Sci USA.2009 Apr 7;106(14):5784-8; WO 2005113595, WO 2006031221, WO 2010106431, WO 2016177339, WO 2016210365, WO 2017044661, WO 2017076308, WO 2017109496, WO 2018132739, WO 2019084538, WO 2019162043, WO 2020086158, and WO 2020086647. Exemplary TCRs and TCR-like antibodies that bind to epitopes of PRAME presented on MHC are described, for example, in International Publication Nos. 2011062634, 2016142783, 2016191246, 2018172533, 2018234319, and 2019109821. Exemplary TCRs and TCR-like antibodies that bind to epitopes of MAGE variants presented on MHC are described, for example, in International Publication Nos. 2007032255, 2012054825, 2013039889, 2013041865, 2014118236, and International Publication Nos. Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented alpha-fetoprotein (AFP) are described, for example, in International Publication No. 2016055785, International Publication No. 2017174822, International Publication No. 2017174823, International Publication No. 2017174824, International Publication No. 2017175006, International Publication No. 2018097951, International Publication No. 2018170338, International Publication No. 2018225732, and International Publication No. 2019204683. Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented SSX2 are described, for example, in International Publication No. 2015011450. Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented SSX2 are described, for example, in International Publication No. 2020 / 063488. Exemplary TCRs and TCR-like antibodies that bind to an epitope of MHC-presented KK-LC-1 (CT83) are described, for example, in WO2017189254.

[0167] Examples of cell therapy include Algenpantucel-L, Sipuleucel-T, (BPX-501) Ribogenreclucel (U.S. Pat. No. 9,089,520, WO 2016100236), AU-105, ACTR-087, activated allogeneic natural killer cells (CNDO-109-AANK), MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, and Immunoglobulins. Leclucel-T, valtalucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral-transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL These include CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

[0168] In some embodiments, the one or more additional co-administered therapeutic agents can be categorized by their mechanism of action, e.g., into the following groups: Drugs that target adenosine deaminase, such as pentostatin or cladribine; · Drugs that target ATM, such as AZD1390; MET-targeting agents such as savortinib, capmatinib, tetponitinib, ABT-700, AG213, JNJ-38877618 (OMO-1), merestinib, HQP-8361, BMS-817378, or TAS-115; Mitogen-activated protein kinase-targeting agents such as antroquinol, binimetinib, cobimetinib, selumetinib, trametinib, uprosertib, mirdametinib (PD-0325901), pimasertib, and refametinib, or agents disclosed in WO 2011008709, WO 2013112741, WO 2006124944, WO 2006124692, WO 2014064215, and WO 2018005435; Zhou et al., Cancer Lett. 2017 Nov 1, 408:130-137; Teli et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70; Gangwall et al. al.,Curr Top Med Chem.(2013)13(9):1015-35;Wu,et al.,Bioorg Med Chem Lett.(2009)19(13):3485-8;Kaila,et al.,Bioorg Med Chem.(2007)15(19):6425-42, or Hu,et al.,Bioorg Med Chem Compounds disclosed in Lett.(2011)21(16):4758-61; Agratimazine besadenovec (ProstAta thymidine, such as thymidine-binding protein (e.g., PancAtak, GliAtak, GMCI, or AdV-tk) kinase-targeting drugs; · Targeted agents that target the interleukin pathway, such as pegilodecakin (AM-0010) (PEGylated IL10) and CA-4948 (IRAK4 inhibitor); Drugs that target members of the cytochrome P450 family, such as letrozole, anastrozole, aminoglutethimide, medistrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), or anastrozole (ARIMIDEX®); Drugs that target CD73, such as CD73 inhibitors (e.g., quemliculstat (AB680)) or anti-CD73 antibodies (e.g., oleculab); ·Drugs that target DKK3, such as MTG-201; · Drugs that target EEF1A2, such as platydysine; Drugs that target EIF4A1, such as rohinitib; · Drugs that target endoglin, such as TRC105 (inflotuximab); Drugs that target exopolitin-1, such as eltanexor; Agents that target fatty acid amide hydrolases, such as the compounds disclosed in WO2017160861; Heat shock protein 90 beta family members such as anlotinib drugs targeting Bar1; · Drugs that target lactoferrin, such as ruxotemitide (LTX-315); agents that target lysyl oxidase, such as the compounds disclosed in U.S. Pat. No. 4,965,288, U.S. Pat. No. 4,997,854, U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, or U.S. Patent Application Publication No. 20040248871; Drugs targeting MAGE family members, such as KITE-718, MAGE-A10C796T, or MAGE-A10TCR; Agents targeting MDM2, such as ALRN-6924, CMG-097, milademethane monotosylate monohydrate (DS-3032b), or AMG-232; · Drugs targeting MDM4, such as ALRN-6924; · Agents targeting Melan-A, such as MART-1 F5 TCR-engineered PBMCs; Drugs that target mesothelin, such as CSG-MESO or TC-210; Drugs that target METAP2, such as M8891 or APL-1202; · Drugs targeting NLRP3, such as BMS-986299; · Drugs that target C=O glutarate dehydrogenase, such as devimistat (CPI-613); · Drugs that target placental growth factors, such as aflibercept; agents targeting SLC10A3, such as the compounds disclosed in WO 2015148954, WO 2012082647, or WO 2017160861; · Agents targeting transforming growth factor alpha (TGFα), such as the compounds disclosed in WO 2019103203; Drugs that target the tumor protein p53, such as kevetrin (a stimulatory factor); · Drugs that target vascular endothelial growth factor A, such as aflibercept; Drugs that target vascular endothelial growth factor receptors, such as fluquinotinib or MP0250; · CA-170 or VISTA-targeting drugs such as HMBD-002; Targeting WEE1, such as adavosertib (AZD-1775) medications; Imatinib, rebastinib, asciminib, ponatinib (ICLUSIG®) ) small molecule inhibitors targeting ABL1; · Small molecule antagonists targeting adenosine receptors, such as CPI-444, AZD-4635, preladenant, etrumadenant (AB928), or PBF-509; · Small molecule inhibitors targeting arachidonate 5-lipoxygenase, such as meclofenamate sodium or zileuton; · Small molecule inhibitors targeting the ATR serine / threonine kinase, such as BAY-937, selalasertib (AZD6738), AZD6783, VX-803, or VX-970 (berzosertib); · Small molecule inhibitors targeting the AXL receptor tyrosine kinase, such as bencentinib (BGB-324), SLC-0211, or gilteritinib (Axl / Flt3); (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, posertinib (HM71224), ibrutinib (Imbruvica), M-2951 ( small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), such as evobrutinib), tirabrutinib (ONO-4059), rilzabrutinib (PRN-1008), spebrutinib (CC-292), becabrutinib, ARQ-531 (MK-1026), SHR-1459, DTRMWXHS-12, or TAS-5315; Small molecule inhibitors targeting neurotrophic receptor tyrosine kinases, such as larotrectinib, entrectinib, or ceritrectinib (LOXO-195); · Small molecule inhibitors targeting the ROS proto-oncogene 1 receptor tyrosine kinase, such as entrectinib, repotrectinib (TPX-0005), or lorlatinib; · Small molecule inhibitors targeting the SRC proto-oncogene non-receptor tyrosine kinase, such as VAL-201, tirbanibulin (KX2-391), or irginatinib maleate (NS-018); · Small molecule inhibitors targeting B-cell lymphoma 2, such as navitoclax (ABT-263), venetoclax (ABT-199, RG-7601), and AT-101 (gossypol); small molecule inhibitors targeting bromodomain and ectodomain (BET) bromodomain-containing proteins, such as ABBV-744, INCB-054329, INCB057643, AZD-5153, ABT-767, BMS-986158, CC-90010, NHWD-870, ODM-207, ZBC246, ZEN3694, CC-95775 (FT-1101), mibebresisb, BI-894999, PLX-2853, PLX-51107, CPI-0610, or GS-5829; · Small molecule inhibitors targeting carbohydrate sulfotransferase 15, such as STNM-01; Small molecule inhibitors that target carbonic anhydrase, such as polmacoxib, acetazolamide, or methazolamide; · Small molecule inhibitors targeting catenin beta 1, such as CWP-291 or PRI-724; · Small molecule antagonists targeting CC motif chemokine receptors, such as CCX-872, BMS-813160 (CCR2 / CCR5), or MK-7690 (Vicriviroc); blixafortide, a small molecule antagonist targeting C-X-C motif chemokine receptors (e.g., CXCR4); Small molecule inhibitors that target cereblon, such as avadomide (CC-122), CC-92480, CC-90009, or iveldomide; · Small molecule inhibitors targeting checkpoint kinase 1, such as SRA737; Imprime PGG (Biothera Pharmaceuticals) small molecule inhibitors that target which complement components; Small molecule inhibitors targeting C-X-C motif chemokine ligands (e.g., CXCL12), such as olaptesed pegol (NOX-A12); · Small molecule inhibitors targeting the cytochrome P450 family, such as ODM-209, LAE-201, seviteronel (VT-464), CFG920, abiraterone, or abiraterone acetate; DEAD box helicases such as spinoxin (RX-5902) small molecule inhibitors targeting 5; small molecule inhibitors targeting DGKα, such as those described in WO 2021130638; · Small molecule inhibitors targeting diablo IAP-binding mitochondrial proteins, such as BI-891065; · Small molecule inhibitors targeting dihydrofolate reductase, such as pralatrexed or pemetrexed disodium; · Small molecule inhibitors targeting DNA-dependent protein kinases, such as MSC2490484A (nedisertib), VX-984, AsiDNA (DT-01), LXS-196, or sotrastaurin; · Small molecule inhibitors targeting MARCKS, such as BIO-11006; · Small molecule inhibitors targeting RIPK1, such as GSK-3145094; · Small molecule inhibitors targeting Rho-associated coiled-coil-containing protein kinases, such as AT13148 or KD025; Small molecule inhibitors that target DNA topoisomerases, such as irinotecan, filtecampegol, or amrubicin; ·Small molecule inhibitors targeting dopamine receptor D2, such as ONC-201; · Small molecule inhibitors targeting histone lysine methyltransferases such as DOT1, such as pinometostat (EPZ-5676); Small molecule inhibitors targeting EZH2, such as tazemetostat, CPI-1205, or PF-06821497; · Small molecule inhibitors targeting fatty acid synthase, such as TVB-2640 (Sagimet Biosciences); · Small molecule inhibitors targeting fibroblast growth factor receptor 2 (FGFR2), such as bemarituzumab (FPA144); Small molecule inhibitors targeting focal adhesion kinase (FAK, PTK2), such as VS-4718, defactinib, or GSK2256098; · Small molecule inhibitors targeting folate receptor 1, such as pralatrexate; · Small molecule inhibitors targeting FOXM1, such as thiostrepton; · Small molecule inhibitors targeting galectin-3, such as berapectin (GR-MD-02); Small molecule antagonists that target the glucocorticoid receptor, such as relacorilant (CORT-125134); CB-839 (telaglenastat) or bis-2-(5-phenyl)- small molecule inhibitors targeting glutaminase, including but not limited to (benylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); Small molecule inhibitors that target the GNRHR, such as elagolix, relugolix, or degarelix; · Small molecule inhibitors targeting EPAS1, such as velzutifan (PT-2977 (Merck & Co.)); Small molecule inhibitors targeting isocitrate dehydrogenase (NADP(+)), such as ivosidenib (AG-120), vorasidenib (AG-881) (IDH1 and IDH2), IDH-305, or enasidenib (AG-221) · Small molecule inhibitors targeting lysine demethylase 1A, such as CC-90011; Small molecule inhibitors targeting MAPK-interacting serine / threonine kinases, such as tomivosertib (eFT-508); · Small molecule inhibitors targeting Notch receptors, such as AL-101 (BMS-906024); · Small molecule inhibitors targeting polo-like kinase 1 (PLK1), such as volasertib or onvansertib; small molecule inhibitors targeting poly(ADP-ribose) polymerase (PARP), such as olaparib (MK7339), rucaparib, veliparib, talazoparib, ABT-767, pamiparib (BGB-290), fluazolepali (SHR-3162), niraparib (JNJ-64091742), stenoparib (2X-121 (e-7499)), simmiparib, IMP-4297, SC-10914, IDX-1197, HWH-340, CEP 9722, CEP-8983, E7016, 3-aminobenzamide, or CK-102; · Small molecule inhibitors targeting the polycomb protein EED, such as MAK683; ·Small molecule inhibitors targeting porcupine O-acyltransferase, such as WNT-974; Small molecule inhibitors targeting prostaglandin-endoperoxide synthase, such as HP-5000, rofecoxib, ketorolac tromethamine, bromfenac sodium, otenaproxyl (ATB-346), mofezolac, GLY-230, TRK-700, diclofenac, meloxicam, parecoxib, etoricoxib, celecoxib, AXS-06, diclofenac potassium, reformulated celecoxib (DRGT-46), AAT-076, MacuOshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumizole, firocoxib, rofecoxib, rutaecarpine, tilmacoxib, zaltoprofen, or imrecoxib; Small molecule inhibitors targeting protein arginine N-methyltransferase, such as MS203, PF-06939999, GSK3368715, or GSK3326595; small molecule inhibitors targeting PTPN11, such as TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630 (SAR442720), or compounds disclosed in WO 2018172984 or WO 2017211303; · Small molecule antagonists that target retinoic acid receptors, such as tamibarotene (SY-1425); · Small molecule inhibitors targeting ribosomal protein S6 kinase B1, such as MSC2363318A; · Small molecule inhibitors targeting S100 calcium-binding protein A9, such as tasquinimod; Uproleselan sodium (GMI-1271) and other small molecule inhibitors targeting lectin E; · Small molecule inhibitors targeting SF3B1, such as H3B-8800; ·Small molecule inhibitors targeting sirtuin-3, such as YC8-02; small molecule inhibitors targeting SMO, such as sonidegib (Odomzo®, formerly LDE-225), vismodegib (GDC-0449), glasdegib (PF-04449913), itraconazole, or patidegib and taladegib; ·Small molecule antagonists targeting somatostatin receptors, such as OPS-201; · Small molecule inhibitors targeting sphingosine kinase 2, such as opaganib (Yeliva®, ABC294640); · Small molecule inhibitors targeting STAT3, such as napabucasin (BBI-608); · Small molecule inhibitors targeting tankyrase, such as G007-LK or stenoparib (2X-121(e-7499)); · Small molecule inhibitors targeting TFGBR1, such as galunisertib and PF-06952229; Thymidylate synthase-targeting drugs such as idetrexed (ONX-0801) targeted small molecule inhibitors; · Small molecule inhibitors targeting the tumor protein p53, such as CMG-097; · Small molecule inhibitors targeting valosin-containing proteins, such as CB-5083; WT1-targeting drugs such as ombipepimut-S (DSP-7888) small molecule inhibitors; · Small molecule agonists that target adenosine receptors, such as namodenoson (CF102); small molecule agonists targeting asparaginase, such as crisantaspase (Erwinase®), GRASPA (ERY-001, ERY-ASP), calaspargase pegol, or pegaspargase; · Small molecule agonists targeting CCAAT enhancer binding protein alpha, such as MTL-501; · Small molecule agonists targeting the cytochrome P450 family, such as mitotane; ·Small molecule agonists targeting DExD / H-box helicase 58, such as RGT-100; · Small molecule agonists targeting the GNRHR, such as leuprorelin acetate, leuprorelin acetate extended-release depot (ATRIGEL), triptorelin pamoate, or goserelin acetate; GRB2-targeting drugs such as prexigebersen (BP1001) small molecule agonists; Small molecule agonists targeting NFE2L2, such as omavelC=Olone (RTA-408); · Small molecule agonists targeting NOD2, such as mifamurtide (liposomal); RAR-related drugs such as cintirorgon (LYC-55716) small molecule agonists targeting the steroid receptor gamma; Small molecule agonists that target the retinoic acid receptor (RAR), such as tretinoin; · Small molecule agonists targeting STING1, such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, cyclic GAMP (cGAMP), or cyclic di-AMP; · Small molecule agonists that target thyroid hormone receptor beta, such as levothyroxine sodium; · Small molecule agonists targeting tumor necrosis factor, such as tasonermin; ·Antisense agents targeting baculovirus IAP repeats containing 5, such as EZN-3042; ·Antisense agents targeting GRB2, such as plexigeneversen; ·Antisense agents targeting heat shock protein 27, such as apatrusen; Danvatirsen (IONIS-STAT3-2.5Rx) antisense agents targeting STAT3; · Gene therapy targeting CC motif chemokine receptors, such as SB-728-T; Interleukin-targeted gene therapies, such as EGENE-001, tavokinogene telseplasmid, nogapendekin alfa (ALT-803), NKTR-255, NIZ-985 (hetIL-15), SAR441000, or MDNA-55; · Antibodies targeting claudin-18, such as claudiximab; ·Antibodies targeting clusterin, such as AB-16B5; ·Antibodies that target complement components, such as ravulizumab (ALXN-1210); ·Antibodies targeting C-X-C motif chemokine ligands, such as BMS-986253 (HuMax-Inflam); · Antibodies targeting Delta-like canonical Notch ligand 4 (DLL4) (DLL4 / VEGF), such as demcizumab and nabicixizumab; ·Antibodies targeting the EPH receptor A3, such as fivatuzumab (KB-004); ·Antibodies targeting epithelial cell adhesion molecules, such as oportuzumab monatox (VB4-845); · Antibodies targeting fibroblast growth factors, such as GAL-F2 and B-701 (vofatamab); ·Antibodies targeting hepatocyte growth factor, such as MP-0250; Canakinumab (ACZ885), gevokizumab (VPM087), CJM-112, guselkumab, talacotuzumab (JNJ-56022473), sil Interleukin-targeting antibodies such as tuximab or tocilizumab; ·Antibodies targeting LRRC15, such as ABBV-085 or cusatuzumab (ARGX-110); ·Antibodies targeting mesothelin, such as BMS-986148, SEL-403, or anti-MSLN-MMAE; Antibodies that target myostatin, such as landogrozumab; Antibodies targeting Notch receptors, such as tarextumab; antibodies targeting TGFB1 (TGFβ1), such as SAR439459, ABBV-151, NIS793, SRK-181, XOMA089, or the compounds disclosed in WO 2019103203; Vaccines targeting fms-related receptor tyrosine kinases, such as HLA-A2402 / HLA-A0201 restricted epitope peptide vaccines · Vaccines targeting heat shock protein 27, such as PSV-AML (PhosphoSynVax); · PD-L1-targeting vaccines such as IO-120+IO-103 (PD-L1 / PD-L2 vaccine) or IO-103; · Vaccines targeting the tumor protein p53, such as MVA-p53; Vaccines targeting WT1, such as WT-1 analog peptide vaccines (WT1-CTL); · Baculovirus IAP repeat-containing 5-targeted cell therapies, such as tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccines; · Carbonic anhydrase-targeted cell therapies such as DC-Ad-GMCAIX; · Cellular therapies targeting CC motif chemokine receptors, such as CCR5-SBC-728-HSPC; Cellular therapies targeting folate hydrolase 1, such as CIK-CAR.PSMA or CART-PSMA-TGFβRDN; · GSTP1-targeted cell therapies such as CPG3-CAR (GLYCAR); HLA-A targeted cell therapy such as FH-MCVA2TCR or NeoTCR-P1; · Cellular therapies targeting interleukins, such as CST-101; · KRAS-targeted cell therapies, such as anti-KRAS G12D mTCR PBL; · MET-targeted cell therapies, such as anti-cMet RNA CAR T; · MUC16-targeted cell therapies, such as JCAR-020; · Cell therapy targeting PD-1, such as PD-1 knockout T-cell therapy (esophageal cancer / NSCLC); ·PRAME-targeted cell therapies such as BPX-701; · Cell therapies targeting the transforming protein E7, such as KITE-439; Cellular therapies targeting WT1, such as WT1-CTL, ASP-7517, or JTCR-016. Exemplary Combination Therapies Lymphoma or leukemia combination therapy

[0169] Some chemotherapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, tin antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-arretin, BMS-345541, bortezomib (VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, brusulfan, campath-1H, carboplatin, carfilzomib (Kyprom), and others. olis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doC=O rubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cycloporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doC=O rubicin, doC=O rubicin hydrochloride, DT-PAC E (dexamethasone, thalidomide, cisplatin, docorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD (hyperfractionated cyclophosphamide), famidine, vincristine, docotrexate, rubicine, dexamethasone, methotrexate, and cytarabine), ICE (ifosfamide, carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafine gadolinium,Mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal C=O rubicin hydrochloride, perifosine, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon α, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab) R-ICE (rituximab and FCM), R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), venetoclax (ABT-199).

[0170] One improved approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® in combination with CHOP.

[0171] The above-mentioned therapies may be supplemented or combined with stem cell transplantation or therapy, including peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, transplantation of in vitro treated peripheral blood stem cells, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation. Combination therapy for non-Hodgkin's lymphoma

[0172] Treatment of non-Hodgkin's lymphoma (NHL), particularly lymphomas of B-cell origin, includes the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doC=O rubicine, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, prednisolone), all optionally including rituximab®), radioimmunotherapy, and combinations thereof, particularly the integration of antibody therapy with chemotherapy.

[0173] Examples of unconjugated monoclonal antibodies for the treatment of NHL / B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0174] Examples of experimental antibody drugs used to treat NHL / B-cell cancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0175] Examples of standard chemotherapy regimens for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doC=O rubicine, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0176] Examples of radioimmunotherapy for NHL / B-cell cancer include yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

[0177] Combination therapy for mantle cell lymphoma

[0178] Curative treatments for mantle cell lymphoma (MCL) include combination chemotherapy, such as CHOP, hyperCVAD, and FCM. These regimens can be supplemented with the monoclonal antibody rituximab to form the combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of the above-mentioned therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0179] An alternative approach to treating MCL is immunotherapy. One type of immunotherapy uses monoclonal antibodies, such as rituximab. Another type of immunotherapy targets the genetic makeup of an individual patient's tumor. Cancer vaccines such as GTOP-99, which is based on the IL-1 receptor agonist, are used.

[0180] An improved approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in sequential treatment with CHOP.

[0181] Other approaches to treating MCL include the combination of autologous stem cell transplantation and high-dose chemotherapy, the administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or the administration of antiangiogenic agents such as thalidomide, particularly in combination with rituximab.

[0182] Another treatment approach is to administer drugs that cause the degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapy drugs.

[0183] Further therapeutic approaches include the administration of mTOR inhibitors, which can cause inhibition of cell proliferation and even cell death. Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and combinations of temsirolimus with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0184] Other recent treatments for MCL have been disclosed, including flavopiridol, palbociclib (PD0332991), R-roscovitine (seliciclib, CYC202), styryl sulfones, obatoclax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CC1-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG).

[0185] Combination therapy for Waldenström macroglobulinemia

[0186] Waldenstrom's Macroglobulinemia Therapeutic agents used to treat WM include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-arretin, bortezomib (VELCADE®), bryostatin 1, busulfan, campas-1H, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, Dexamethasone, docetaxel, dolastatin 10, doC=O rubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (e.g., tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD2 0, motexafine gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal C=O rubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, urocuprumab, veltuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0187] Examples of therapeutic approaches used to treat WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biologic therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, myeloablative with stem cell support, transplantation of in vitro processed peripheral blood stem cells, umbilical cord blood transplantation, immunoenzyme techniques, low-LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation. Combination therapy for diffuse large B-cell lymphoma (DLBCL)

[0188] Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doC=O rubicine, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and RICE. In some embodiments, therapeutic agents used to treat DLBCL include liximab (Rituxan®), cyclophosphamide, doC=O rubicine hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin®), prednisone, bendamustine, ifosfamide, carboplatin, etoposide, ibrutinib, polatuzumab vedotin piiq, bendamustine, copanlisib, lenalidomide (Revlimid®), dexamethasone, cytarabine, cisplatin, Yescarta®, Kymriah®, Polivy® (polatuzumab vedotin), BR (bendamustine (Treanda®)), gemcitabine, oxiplatin, oxaliplatin, tafasitamab, polatuzumab, cyclophosphamide, or a combination thereof.In some embodiments, therapeutic agents used to treat DLBCL include R-CHOP (rituximab + cyclophosphamide + docosahexaenoic acid hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone), rituximab + bendamustine, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), rituximab + lenalomide, R-DHAP (rituximab + dexamethasone + high-dose cytarabine (Ara C) + cisplatin), Polivy® (polatuzumab vedotin) + BR (bendamustine (Treanda®) and rituximab (Rituxan®), R-GemOx (gemcitabine + oxaliplatin + rituximab), Tafa-Len (tafasitamab + lenalidomide), tafasitamab + Revlimid®, polatuzumab + bendamustine, gemcitabine + oxaliplatin, R-EPOCH (rituximab + ethyl phosphate) In some embodiments, therapeutic agents used to treat DLBCL include tafasitamab, glofitamab, epocoristine, tafasitamab, glofitamab, vincristine sulfate (Oncovin®) + cyclophosphamide + doC=O rubicin hydrochloride (hydroxydaunorubicin), or CHOP (cyclophosphamide + doC=O rubicin hydrochloride (hydroxydaunorubicin) + vincristine sulfate (Oncovin®) + prednisone). Examples of such agents include tamab, Lonca-T (loncatuximab tesirin), Debio-1562, polatuzumab, Yescarta, JCAR017, ADCT-402, brentuximab vedotin, MT-3724, odronextamab, Auto-03, Allo-501A, or TAK-007. Combination therapy for chronic lymphocytic leukemia

[0189] Therapeutic agents used to treat chronic lymphocytic leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doC=O rubicine, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, and combination chemotherapy and chemoimmunotherapy, including common combination regimens such as CVP, R-CVP, ICE, R-ICE, FCR, and FR. High Risk Myelodysplastic Syndrome (HR MDS) ) Combination therapy

[0190] Therapeutic agents used to treat HR MDS include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, and combinations thereof. In some embodiments, combinations include cytarabine plus daunorubicin and cytarabine plus idarubicin. In some embodiments, therapeutic agents used to treat HR MDS include pevonedistat, venetoclax, sabatolimab, guadecitabine, rigosertib, ivosidenib, enazidenib, selinexor, BGB324, DSP-7888, or SNS-301. Combination therapy for Low Risk Myelodysplastic Syndrome (LR MDS)

[0191] Therapeutic agents used to treat LR MDS include lenalidomide, azacitidine, and combinations thereof. In some embodiments, therapeutic agents used to treat LR MDS include roxadustat, raspatercept, imetelstat, LB-100, or rigosertib. Acute myeloid leukemia (AML) combination therapy

[0192] Therapeutic agents used to treat AML include cytarabine, idarubicin, daunorubicin, midostaurin (Rydapt®), venetoclax, azacitidine, ivasidenib, gilteritinib, enadidenib, low-dose cytarabine (LoDAC), mitoxantrone, fludarabine, granulocyte colony-stimulating factor, idarubicin, gilteritinib (Xospata®), enadidenib (Idhifa®), ivosidenib (Tibsovo®), decitabine (Dacogen®), mitoxantrone, etoposide, gemtuzumab ozogamicin (Mylotarg®), glasdegib (Daurismo®), and combinations thereof. In some embodiments, the therapeutic agents used to treat AML include FLAG-Ida (fludarabine, cytarabine (Ara-C), granulocyte-colony stimulating factor (G-CSF), and idarubicin), cytarabine plus idarubicin, cytarabine plus idarubicin, and cytarabine plus idarubicin. These include unorubicin and midostaurin, venetoclax and azacitidine, cytarabine and daunorubicin, or MEC (mitoxantrone, etoposide, and cytarabine). In some embodiments, therapeutic agents used to treat AML include pevonedistat, venetoclax, sabatolimab, eprenetapopt, or renzoparlimab. Multiple myeloma (MM) combination therapy

[0193] Therapeutic agents used to treat MM include lenalidomide, bortezomib, dexamethasone, daratumumab (Darzalex®), pomalidomide, cyclophosphamide, carfilzomib (Kyprolis®), elotuzumab (Empliciti), and combinations thereof. In some embodiments, therapeutic agents used to treat MM include RVS (lenalidomide + bortezomib + dexamethasone), RevDex (lenalidomide + dexamethasone), CYBORD (cyclophosphamide + bortezomib + dexamethasone), Vel / Dex (bortezomib + dexamethasone), or PomDex (pomalidomide + low-dose dexamethasone). In some embodiments, therapeutic agents used to treat MM include JCARH125, TAK-573, belantamab-m, ide-cel (CAR-T). Breast cancer combination therapy

[0194] Therapeutic agents used to treat breast cancer include albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doC=O rubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, PEGylated liposomal doC=O rubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat breast cancer (e.g., HR+ / - / HER2+ / -) include trastuzumab (Herceptin®), pertuzumab (Perjeta®), docetaxel, carboplatin, palbociclib (Ibrance®), letrozole, trastuzumab emtansine (Kadcyla®), fulvestrant (Faslodex®), olaparib (Lynparza®), eribulin, tucatinib, capecitabine, lapatinib, everolimus (Afinitor®), exemestane, eribulin mesylate (Halaven®), and combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab + pertuzumab + docetaxel, trastuzumab + pertuzumab + docetaxel + carboplatin, palbociclib + letrozole, tucatinib + capecitabine, lapatinib + capecitabine, palbociclib + fulvestrant, or everolimus + exemestane. In some embodiments, therapeutic agents used to treat breast cancer include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan, DS-1062, enfortumumab vedotin (Padcev®), balixafortide, elacestrant, or combinations thereof. In some embodiments, therapeutic agents used to treat breast cancer include balixafortide + eribulin. Triple Negative Breast Cancer (TNBC) Combination Therapy

[0195] Therapeutic agents used to treat TNBC include atezolizumab, cyclophosphamide, docetaxel, doC=Orubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. In some embodiments, therapeutic agents used to treat TNBC include olaparib (Lynparza®), atezolizumab (Tecentriq®), paclitaxel (Abraxane®), eribulin, bevacizumab (Avastin®), carboplatin, gemcitabine, eribulin mesylate (Halaven®), sacituzumab govitecan (Trodelvy®), pembrolizumab (Keytr In some embodiments, therapeutic agents for treating TNBC include atezolizumab + paclitaxel, bevacizumab + paclitaxel, carboplatin + paclitaxel, carboplatin + gemcitabine, or paclitaxel + gemcitabine. In some embodiments, therapeutic agents used to treat TNBC include eliyaspase, capivasertib, alpelisib, rucaparib + nivolumab, atezolumab + paclitaxel + gemcitabine + capecitabine + carboplatin, ipatasertib + paclitaxel, radilatuzumab vedotin + pembrolimab, durvalumab + DS-8201a, trilaciclib + gemcitabine + carboplatin. In some embodiments, therapeutic agents used to treat TNBC include trastuzumab deruxtecan (Enhertu®), datopotamab deruxtecan (DS-1062), enfortumab vedotin (Padcev®), balixafortide, adaglioxad simorenin (adaglioxad simolenin), neripepimut (NeuVax®), nivolumab (Opdivo®), rucaparib, toripalimab (Tuoyi®), camrelizumab, capivasertib, durvalumab (Imfinzi®), and combinations thereof. In some embodiments, therapeutic agents used to treat TNBC include nivolumab + rucaparib, bevacizumab (Avastin®) + chemotherapy, toripalimab + paclitaxel, toripalimab + albumin-bound paclitaxel, camrelizumab + chemotherapy, pembrolizumab + chemotherapy, balixafortide + eribulin, durvalumab + trastuzumab deruxtecan, durvalumab + paclitaxel, or capivasertib + paclitaxel. Bladder cancer combination therapy

[0196] Therapeutic agents used to treat bladder cancer include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), erdafitinib, eganelisib, lenvatinib, bempegaldesleukin (NKTR-214), or combinations thereof. In some embodiments, therapeutic agents used to treat bladder cancer include eganelisib plus nivolumab, pembrolizumab (Keytruda®) plus enfortumumab vedotin (Padcev®), nivolumab plus ipilimumab, duravalumab plus tremelimumab, lenvatinib plus pembrolizumab, enfortumumab vedotin (Padcev®) plus pembrolizumab, and bempegaldesleukin plus nivolumab. Colorectal cancer (CRC) combination therapy

[0197] Therapeutic agents used to treat CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab (Avastin®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf (Orcantas®), XELOX, FOLFOXIRI, or a combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, therapeutic agents used to treat CRC include binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, and nivolumab + ipilimumab. Combination therapy for esophageal and gastroesophageal junction cancer

[0198] Therapeutic agents used to treat esophageal cancer and esophagogastric junction cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. In some embodiments, therapeutic agents used to treat gastroesophageal junction cancer (GEJ) include herceptin, cisplatin, 5-FU, ramicurimab, or paclitaxel. In some embodiments, Therapeutic agents used to treat GEJ cancer include ALX-148, AO-176, or IBI-188. Gastric cancer combination therapy

[0199] Therapeutic agents used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidines, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. Head and neck cancer combination therapy

[0200] Therapeutic agents used to treat head and neck cancer include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof.

[0201] Therapeutic agents used to treat head and neck squamous cell carcinoma (HNSCC) include pembrolizumab, carboplatin, 5-FU, docetaxel, cetuximab (Erbitux®), cisplatin, nivolumab (Opdivo®), and combinations thereof. In some embodiments, therapeutic agents used to treat HNSCC include pembrolizumab + carboplatin + 5-FU, cetuximab + cisplatin + 5-FU, cetuximab + carboplatin + 5-FU, cisplatin + 5-FU, and carboplatin + 5-FU. In some embodiments, therapeutic agents used to treat HNSCC include durvalumab, durvalumab plus tremelimumab, nivolumab plus ipilimumab, robaleucel, pembrolizumab, pembrolizumab plus epacadostat, GSK3359609 plus pembrolizumab, lenvatinib plus pembrolizumab, retifanlimab, retifanlimab plus enobituzumab, ADU-S100 plus pembrolizumab, epacadostat plus nivolumab plus ipilimumab / lirilumab. Combination therapy for non-small cell lung cancer

[0202] Therapeutic agents used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat NSCLC include alectinib (Alecensa®), dabrafenib (Taf Inlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), entrectinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), nab-paclitaxel (Abraxane®), ramucirumab (Cyramza®), doxorubicin (DTX®), rifametinib (RTX®), rifampin (RIFF ... In some embodiments, therapeutic agents used to treat NSCLC include cetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif®), nivolumab (Opdivo®), gefitinib (Iressa®), and combinations thereof. In some embodiments, therapeutic agents used to treat NSCLC include dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab ... Lorisumab + carboplatin + nab-paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + nab-paclitaxel, cisplatin + Gemzar, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nab-paclitaxel, or pemetrexed + cisplatin + cisplatin In some embodiments, therapeutic agents used for NSCLC include datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), enfortumab vedotin (Padcev®), durvalumab, canakinumab, cemiplimab, nogapendekin alfa, avelumab, tiragolumab, donbanalimab, vibostolimab, osipellimab, or a combination thereof.In some embodiments, the therapeutic agents used to treat NSCLC include datopotamab deruxtecan plus pembrolizumab, datopotamab deruxtecan plus durvalumab, durvalumab plus tremelimumab, pembrolizumab plus lenvatinib plus pemetrexed, pembrolizumab plus olaparib, nogapendequin alfa (N-803) plus pembrolizumab, tiragolumab plus atezolizumab, vibostolimab plus pembrolizumab, or osipellimab plus tislelizumab. Small cell lung cancer combination therapy

[0203] Therapeutic agents used to treat small cell lung cancer (SCLC) include atezolizumab, bendamustimeth, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. In some embodiments, therapeutic agents used to treat SCLC include atezolizumab, carboplatin, cisplatin, etoposide, paclitaxel, topotecan, nivolumab, durvalumab, trilaciclib, or a combination thereof. In some embodiments, the therapeutic agents used to treat SCLC include atezolizumab plus carboplatin plus etoposide, atezolizumab plus carboplatin, atezolizumab plus etoposide, or carboplatin plus paclitaxel. Ovarian cancer combination therapy

[0204] Therapeutic agents used to treat ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doC=O rubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doC=O rubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof. Pancreatic cancer combination therapy

[0205] Therapeutic agents used to treat pancreatic cancer include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane®), FOLFIRINOX, and combinations thereof. In some embodiments, therapeutic agents used to treat pancreatic cancer include 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, leucovorin + nanoliposomal irinotecan, and gemcitabine + nab-paclitaxel. Prostate cancer combination therapy

[0206] Therapeutic agents used to treat prostate cancer include enzalutamide (Xtandi®), leuprolide, trifluridine, tipiracil (Lonsurf®), cabazitaxel, prednisone, abiraterone (Zytiga®), docetaxel, mitoxantrone, bicalutamide, LHRH, flutamide, ADT, sabizablin (Veru-111), and combinations thereof. In some embodiments, therapeutic agents used to treat prostate cancer include enzalutamide + leuprolide, trifluridine + tipiracil (Lonsurf®), cabazitaxel + prednisone, abiraterone + prednisone, docetaxel + prednisone, mitoxantrone + prednisone, bicalutamide + LHRH, flutamide + LHRH, leuprolide + flutamide, and abiraterone + prednisone + ADT. Additional Illustrated Combination Therapies

[0207] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents chosen from a PI3K inhibitor, a Trop-2 binding agent, a CD47 antagonist, a SIRPα antagonist, a FLT3R agonist, a PD-1 antagonist, a PD-L1 antagonist, an MCL1 inhibitor, a CCR8 binding agent, an HPK1 antagonist, a DGKα inhibitor, a CISH inhibitor, a PARP-7 inhibitor, a Cbl-b inhibitor, a KRAS inhibitor (e.g., a KRAS G12C or G12D inhibitor), a KRAS degrader, a β-catenin degrader, a Helios degrader, a CD73 inhibitor, an adenosine receptor antagonist, a TIGIT antagonist, a TREM1 binding agent, a TREM2 binding agent, a CD137 agonist, a GITR binding agent, an OX40 binding agent, and a CAR-T cell therapy.

[0208] In some embodiments, the antibodies and / or fusion proteins provided herein are administered in combination with a PI3Kδ inhibitor (e.g., idelalisib), an anti-Trop-2 antibody drug conjugate (e.g., sacituzumab govitecan, datopotamab deruxtecan (DS-1062)), an anti-CD47 antibody, or CD47-blocking agents (e.g., magrolimab, DSP-107, AO-176, ALX-148, retaplimab (IBI-188), lemzoparlimab, TTI-621, TTI-622), anti-SIRPα antibodies (e.g., GS-0189), FLT3L-Fc fusion proteins (e.g., GS-3583), anti-PD-1 antibodies (pembrolizumab, nivolumab, zinbelimab), small molecule PD-L1 inhibitors (e.g., For example, GS-4224), anti-PD-L1 antibodies (for example, atezolizumab, avelumab), small molecule MCL1 inhibitors (for example, GS-9716), small molecule HPK1 inhibitors (for example, GS-6451), HPK1 degraders (PROTACs; for example, ARV-766), small molecule DGKα inhibitors, small molecule CD73 inhibitors (for example, quemliculstat (AB680)), anti-CD73 antibodies (for example, oleculab), double A inhibitors (for example, cerebrospinal fluid (CF)), and anti-PD-L1 antibodies (for example, atezolizumab, avelumab). 2a / A 2b Adenosine receptor antagonists (e.g., etormadenant (AB928)), anti-TIGIT antibodies (e.g., tiragolumab, vibostolimab, donbanalimab, AB308), anti-TREM1 antibodies (e.g., PY159), anti-TREM2 antibodies (e.g., PY314), CD137 agonists (e.g., AGEN-2373), G It is administered in conjunction with one or more therapeutic agents selected from an ITR / OX40 binding agent (e.g., AGEN-1223) and a CAR-T cell therapy (e.g., axicabtagene ciloreucel, brexcabtagene outrucel, tisagenlecleucel).

[0209] In some embodiments, the antibodies and / or fusion proteins provided herein are administered with one or more therapeutic agents selected from idelalisib, sacituzumab govitecan, magrolimus, GS-0189, GS-3583, zimberelimab, GS-4224, GS-9716, GS-6451, chemliglustat (AB680), etramadenant (AB928), donvanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicabtagene ciloleucel, and brexcabtagene autoleucel. III. Pharmaceutical Compositions

[0210] While it is possible for the active ingredients to be administered alone, it may be preferable to present them as pharmaceutical formulations (compositions). Formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and, optionally, other additional therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0211] Formulations include those suitable for the aforementioned routes of administration. Formulations may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with inert ingredients (e.g., carriers, pharmaceutical excipients, etc.), which constitute one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0212] In certain embodiments, formulations suitable for oral administration are presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient.

[0213] In certain embodiments, pharmaceutical formulations comprise one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers or additives and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable additives suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. may be used alone or in combination with wax.

[0214] The amount of active ingredient combined with inactive ingredients to produce a dosage form will vary depending on the host treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains about 1 to 1000 mg of active ingredient formulated with an appropriate and convenient amount of carrier material (e.g., inactive or excipient material). In certain embodiments, the carrier material ranges from about 5 to about 95% (weight:weight) of the total composition. In some embodiments, the pharmaceutical compositions described herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1 to 200 mg, 1 to 100 mg, or 1 to 50 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain about 400 mg or less of a compound of Formula I. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0215] It will be understood that in addition to the ingredients particularly mentioned above, the formulations disclosed herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0216] There is further provided a veterinary composition comprising at least one active ingredient as defined above together with a veterinary carrier.

[0217] A veterinary carrier may be a solid, liquid, or gaseous substance that is useful for the purpose of administering the composition and is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0218] The effective dose of the active ingredient will depend, at least, on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (low doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. IV. Route of Administration

[0219] One or more compounds of Formula I (herein referred to as active ingredients) or pharmaceutically acceptable salts thereof are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally. Thus, in one embodiment, the pharmaceutical compositions described herein are in oral dosage form. In certain embodiments, the pharmaceutical compositions described herein are in oral solid dosage form. Formulation Example 1

[0220] Hard gelatin capsules are prepared containing the following ingredients: [Table 1]

[0221] The above ingredients are mixed and filled into a hard gelatin capsule. Formulation Example 2

[0222] A tablet formulation is prepared using the following ingredients: [Table 2]

[0223] The ingredients are blended and compressed to form a tablet. Formulation Example 3

[0224] A dry powder inhaler formulation is prepared containing the following ingredients: [Table 3]

[0225] The active ingredient is mixed with lactose and the mixture is added to a dry powder inhaler device. Formulation Example 4

[0226] Tablets, each containing 30 mg of active ingredient, are prepared as follows: [Table 4]

[0227] The active ingredient, starch, and cellulose are passed through a 20-mesh US sieve and thoroughly mixed. The solution of polyvinylpyrrolidone is mixed with the resulting powder, which is then passed through a 16-mesh US sieve. The granules thus produced are dried at 50-60°C and passed through a 16-mesh US sieve. Sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a 30-mesh US sieve, are then added to the granules, which, after mixing, are compressed on a tablet press to yield tablets each weighing 120 mg. Formulation Example 5

[0228] Suppositories, each containing 25 mg of active ingredient, are made as follows: [Table 5]

[0229] The active ingredient is passed through a 60 mesh US sieve and premelted using minimal heat. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 6

[0230] Suspensions, each containing 50 mg of active ingredient per 5.0 mL dose, are made as follows: [Table 6]

[0231] The active ingredient, sucrose, and xanthan gum are blended and passed through a 10-mesh US sieve, then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose. The sodium benzoate, flavor, and color are diluted with some water and added with stirring. Sufficient water is then added to produce the required volume. Formulation Example 7

[0232] The subcutaneous formulation can be prepared as follows. [Table 7] Formulation Example 8

[0233] An injectable formulation having the following composition is prepared. [Table 8] Formulation Example 9

[0234] A topical formulation is prepared having the following composition: [Table 9]

[0235] All of the above ingredients except water are combined and heated with stirring to 60° C. A sufficient quantity of water at 60° C. is then added with vigorous stirring to emulsify the ingredients, and water qs 100 g is then added. Formulation Example 10

[0236] sustained release composition [Table 10]

[0237] The sustained-release formulation of the present disclosure can be prepared as follows: The compound, pH-dependent binder, and optional additives are intimately mixed (dry blended). The dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base, which is sprayed into the blended powder. The granules are dried, sieved, mixed with an optional lubricant (such as talc or magnesium stearate), and compressed into tablets. A preferred aqueous solution of a strong base is a solution of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of a water-miscible solvent, such as a lower alcohol). The resulting tablets may be coated with an optional film-forming agent for identification, taste-masking purposes, and to improve swallowability. The film-forming agent is typically present in an amount ranging from 2% to 4% of the tablet weight. Suitable film-forming agents are well known in the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymer (dimethylaminoethyl methacrylate / methyl-butyl methacrylate copolymer—Eudragit® E—RohmPharma), and the like. These film-forming agents may optionally contain colorants, plasticizers, and other auxiliary ingredients.

[0238] The compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression. Tablet size depends primarily on the amount of compound in the tablet. Tablets contain 300-1100 mg of compound free base. Preferably, tablets contain amounts of compound free base in the ranges of 400-600 mg, 650-850 mg, and 900-1100 mg.

[0239] The time the compound-containing powder is wet-mixed is controlled to affect the dissolution rate. Preferably, the total powder mixing time, i.e., the time the powder is exposed to the sodium hydroxide solution, is in the range of 1 to 10 minutes, preferably 2 to 5 minutes. After granulation, the particles are removed from the granulator and placed in a fluidized bed dryer to dry at about 60°C. Formulation Example 11

[0240] A tablet formulation is prepared using the following ingredients: [Table 11]

[0241] The ingredients are blended and compressed to form a tablet. V. List of Abbreviations and Acronyms [Table 12-1] [Table 12-2] General Scheme [Example]

[0242] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent well-functioning techniques in the practice of the present disclosure and can therefore be considered to constitute specific modes for its practice. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments disclosed that will still achieve similar or similar results without departing from the spirit and scope of the present disclosure. i. General Scheme A [ka] ii. General Scheme B [ka] iii. General Scheme C [ka] Example

[0243] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent well-functioning techniques in the practice of the present disclosure and can therefore be considered to constitute specific modes for its practice. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments disclosed that will still achieve similar or similar results without departing from the spirit and scope of the present disclosure. iv. General Scheme A [ka] v. General Scheme B [ka] vi. General Scheme C [ka] ii. Synthesis Examples Example 1 Preparation of 2-(4-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)pentyl)-6-(5-(trifluoromethyl)pyridin-2-yl)isoquinolin-1(2H)-one [ka]

[0244] Step 1. To a stirred solution of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate (200 mg, 0.984 mmol) and triethylamine (199 mg, 1.97 mmol) in dichloromethane (4.50 mL) at 0°C, p-toluenesulfonyl chloride (188 mg, 0.984 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with 0-100% EtOAc in hexanes to give 4-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate. ES / MS: m / z 380.4 [M+Na] + .

[0245] Step 2. To a mixture of 6-bromo-2H-isoquinolin-1-one (55.0 mg, 0.245 mmol) and 4-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate (102 mg, 0.285 mmol) in DMF (0.70 mL) was added CsCO (160 mg, 0.491 mmol), and the reaction was stirred at room temperature for 18 hours. Upon completion, the mixture was diluted with EtOAc, washed with water, washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product. The crude residue was purified using column chromatography eluting with 0-100% EA in hexanes to give tert-butyl N-[4-(6-bromo-1-oxo-2-isoquinolyl)-1-methyl-butyl]carbamate. ES / MS: m / z 411.2 [M+H] + .

[0246] Step 3. Dissolution of tert-butyl N-[4-(6-bromo-1-oxo-2-isoquinolyl)-1-methyl-butyl]carbamate (106 mg, 0.259 mmol), [5-(trifluoromethyl)-2-pyridyl]boronic acid (148 mg, 0.777 mmol), Pd(dppf)Cl2 (21.4 mg, 0.026 mmol), and KOAc (76.2 mg, 0.777 mmol) in dioxane (2.0 mL) and water (0.3...

Claims

[Claim 1] The invention described in the specification.

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