# US 10,945,994 B2 · Combinations comprising a pyrrolidine-2,5-dione IDO1 inhibitor and an anti-body > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,945,994 B2 - Document ID: US10945994B2 - Status: Granted - Kind: B2 - Application number: 15/573,190 - Filed: 2016-05-12 - Published: 2018-05-10 - Granted: 2021-03-16 - Earliest claimed: 2015-05-14 - Assignees: Pfizer Inc.; Iteos Therapeutics - Applicants: Pfizer Inc.; iTeos Therapeutics - Inventors: Manfred Kraus; Sandra Cauwenberghs; Stefano Crosignani; Gregory Driessens - Web page: https://patentgrep.com/patent/US10945994B2 ## CPC - A61K 31/404: Indoles, e.g. pindolol - A61K 31/337: having four-membered rings, e.g. taxol - A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) - A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum - A61K 39/39558: {against tumor tissues, cells, antigens} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 31/12: Antivirals - A61P 35/00: Antineoplastic agents - C07K 16/2818: {against CD28 or CD152} - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration} - A61K 2039/505: {comprising antibodies} - A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Combinations of an IDO1 inhibitor (e.g., a 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione compound), with an anti-PD1 antibody or anti-PD-L1 antibody, and an anti-4-1BB antibody, as selected anti-cancer or anti-viral agents are provided. Also provided are use of these combinations for the treatment and/or prevention of cancer and endometriosis. ## Claims ### Claim 1 A combination regimen useful in cancer treatment comprising the co-administration to a subject in need thereof of (a) at least one indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, (b) at least one second active component which is an immunomodulatory agent selected from an anti-PD-1 or anti-PD-L1 antibody, and (c) at least a third active component which is an anti-4-1BB antibody, wherein the IDO1 inhibitor is a racemic 3-(5-fluoro -1H-indol-3-yl) pyrrolidine-2,5-dione, the (R)- enantiomer thereof, the (S)-enantiomer thereof, or a mixture thereof. ### Claim 2 (depends on 1) The combination regimen according to claim 1, wherein the IDO1 inhibitor and the anti-PD-1 or anti-PD-L1 antibody are administered to the subject substantially simultaneously. ### Claim 3 (depends on 1) The combination regimen according to claim 1, wherein the IDO1 inhibitor and the anti-PD-1 or anti-PD-L1 antibody are delivered sequentially. ### Claim 4 (depends on 1) The combination regimen according to claim 1, wherein the IDO1 inhibitor and the anti-PD-1 or anti-PD-L1 antibody are delivered via different routes. ### Claim 5 (depends on 1) The combination regimen according to claim 1, wherein the IDO1 inhibitor is administered to the subject orally. ### Claim 6 (depends on 1) The combination regimen according to claim 1, wherein the anti-PD-1 or anti-PD-L1 is administered to the subject via injection. ### Claim 7 (depends on 1) The combination regimen according to claim 1, wherein the IDO1 inhibitor is selected from one or more of 3-(5-fluoro -1H-indol-3-yl)pyrrolidine-2,5-dione in free base form, 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione racemate, an (S)-enantiomer of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or an (R)-enantiomer of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione. ### Claim 8 (depends on 7) The combination regimen according to claim 7, wherein the 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione racemate is used in the combination, said racemate comprising about 50% (R)- and (S)-enantiomers. ### Claim 9 (depends on 7) The combination regimen according to claim 7, wherein a mixture of (R)- and (S)-enantiomers of 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione are used in the combination. ### Claim 10 (depends on 9) The combination regimen according to claim 9, wherein greater than 50% of the (R)-enantiomer is used. ### Claim 11 (depends on 9) The combination regimen according to claim 9, wherein the mixture of (R) and (S) enantiomers comprises at least 95% to 100% of the (R)-enantiomer. ### Claim 12 (depends on 1) The combination according to claim 1, wherein the cancer is selected from malignant melanoma, acute myelogenous leukemia, pancreatic, colorectal, lung, prostate, cervical, brain, liver, head and neck, endometrial, ovarian cancers or breast cancer. ### Claim 13 (depends on 1) The combination according to claim 1, wherein the subject has a chronic viral infection associated with oncogenesis. ### Claim 14 (depends on 1) The combination regimen according to claim 1, wherein the cancer is breast cancer. ### Claim 15 (depends on 1) The combination regimen according to claim 1, wherein the anti-PD-L1 antibody is avelumab. ### Claim 16 (depends on 1) The combination regimen according to claim 1 which comprises co-administration of a further active component which is an immunomodulatory agent selected from an anti-CTLA4 antibody, an anti-OX-40 antibody, an anti-cancer vaccine, an P-cadherin LP-Dual-Affinity Re-Targeting protein, a TDO inhibitor, a signal modulating inhibitor, an antibody-drug conjugate (ADC), ibrutinib or a chemotherapeutic. ### Claim 17 (depends on 16) The combination regimen according to claim 16, wherein the immunomodulatory agent is an anti-CTLA4 antibody. ### Claim 18 (depends on 17) The combination regimen according to claim 17, wherein the anti-CTLA4 antibody is ipilimumab or tremelimumab. ### Claim 19 (depends on 16) The combination regimen according to claim 16, wherein the further active component is the anti-cancer vaccine. ### Claim 20 (depends on 16) The combination regimen according to claim 16, wherein the further active component is the signal modulating inhibitor, wherein the signal modulating inhibitor is selected from a Pi3K/mTOR inhibitor, a Pi3K-alpha selective inhibitor, an MEK inhibitor, an enhancer of zeste homolog 2 (EZH2) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor (VEGF) inhibitor, or a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. ### Claim 21 (depends on 20) The combination regimen according to claim 20, wherein the signal modualting inhibitor is the Pi3k/mTOR inhibitor which is gedatolisib. ### Claim 22 (depends on 20) The combination regimen according to claim 20, wherein the signal modulating inhibitor is a Pi3K-alpha selective inhibitor. ### Claim 23 (depends on 20) The combination regimen according to claim 20, wherein the signal modulating inhibitor is the selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6, which is palbociclib. ### Claim 24 (depends on 16) The combination regimen according to claim 16, wherein the further active component is a chemotherapeutic which is an alkylating agent. ### Claim 25 (depends on 24) The combination regimen according to claim 24, wherein the chemotherapeutic is temozolomide. ### Claim 26 (depends on 24) The combination regimen according to claim 24, wherein the chemotherapeutic is docetaxel.