Claims for Patent: 9,556,167

Summary for Patent: 9,556,167

Title:	TLR-agonist-conjugated antibody recruiting molecules (TLR-ARMs)
Abstract:	The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus (CBT) and Toll-like receptor agonist (TLR) through a linker and a multifunctional connector group or molecule.
Inventor(s):	Spiegel; David (New Haven, CT), Fitzgerald; Kelly (New Haven, CT)
Assignee:	YALE UNIVERSITY (New Haven, CT)
Application Number:	14/397,995
Patent Claims:	1. A compound according to the chemical structure: ##STR00075## Wherein [ABT] is an antibody binding moiety comprising a hapten which is capable of binding to an antibody in a patient according to the chemical formula: ##STR00076## Where Y' is H or NO.sub.2; X is O, CH.sub.2, NR.sup.1, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group, or a --C(O)(C.sub.1-C.sub.3) group; X' is CH.sub.2, O, N--R'' or S; R.sup.1' is H or C.sub.1-C.sub.3 alkyl; Z is a bond, a monosaccharide, disaccharide, oligosaccharide, glycoprotein or glycolipid; X.sup.b is a bond, O, CH.sub.2, NR.sup.1 or S; X'' is O, CH.sub.2, NR.sup.1; X.sub.R is O or S; X.sub.M is O or S; R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group or a --C(O)(C.sub.1-C.sub.3) group, or a group according to the chemical structure: ##STR00077## wherein each of said DNP groups is a dinitrophenyl group linked through an amino group or a thio group as indicated to the amino acid moiety; [CBT] is a cell binding moiety capable of binding to prostate specific membrane antigen (PSMA) on the cell surface of a cancer cell in said patient according to the chemical formula: ##STR00078## Where X.sub.1 and X.sub.2 are each independently CH.sub.2, O, NH or S; X.sub.3 is O, CH.sub.2, NR.sup.1, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group, or a --C(O)(C.sub.1-C.sub.3) group; k is an integer from 0 to 20; [TLR] is a Toll-like Receptor (TLR) agonist moiety according to the chemical structure; ##STR00079## Where R.sup.2TLR is moiety which is 3-4 atoms in length wherein said atoms are carbon, oxygen sulfur or nitrogen, said nitrogen being substitutable by H and or a C.sub.1-C.sub.3 alkyl group; ##STR00080## and X.sup.TLR is O, S or N--R.sup.NTLR where R.sup.NTLR is H or a C.sub.1-C.sub.3 alkyl group; or [TLR] is a group according to the chemical structure: ##STR00081## where X.sup.TLR is the same as above, or a salt form thereof; L.sub.1 is at least one linker group which links [MULTICON] to [ABT] in aid compound; L.sub.2 is at least one linker group which links [MULTICON] to [CBT] in said compound; L.sub.3 is at least one linker group which binds [MULTICON] to [TLR] in said compound; Wherein any one or more of L.sub.1, L.sub.2 and L.sub.3 optionally is or comprises a labile linker; [MULTICON] is a multifunctional connector molecule which binds to said L.sub.1, L.sub.2 and L.sub.3 linker groups, said multifunctional connector molecule having the chemical structure: ##STR00082## Wherein each Y.sub.4 is N; and Each X'' is N--H; Each n, n' and n'' in a molecule is independently an integer from 1 to 15, and Each of NL1, NL2 and NL3 is independently an integer from 1 to 10 wherein n.gtoreq.NL1, n'.gtoreq.NL2 and n''.gtoreq.NL3, or a pharmaceutically acceptable salt, stereoisomer, diastereomer, enantiomer, solvate or polymorph thereof. 2. The compound according to claim 1 wherein n, n', n'', NL1, NL2 and NL3 are each 1; [ABT] is an antibody binding moiety according to the chemical formula: ##STR00083## Where Y' is H; X is O, CH.sub.2, NR.sup.1, S(O), S(O).sub.2, --S(O).sub.2O, --OS(O).sub.2, or OS(O).sub.2O; R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group, or a --C(O)(C.sub.1-C.sub.3) group; X' is CH.sub.2, O, N--R.sup.1' or S; R.sup.1' is H or C.sub.1-C.sub.3 alkyl; Z is a bond, a monosaccharide, disaccharide, oligosaccharide, glycoprotein or glycolipid; X.sub.R is O or S; X.sub.M is O or S; R.sup.1 is H, a C.sub.1-C.sub.3 alkyl group or a --C(O)(C.sub.1-C.sub.3) group; [CBT] is a cell binding moiety according to the chemical formula: ##STR00084## k is 1, 2, 3, 4, 5 or 6; [TLR] is the same as in claim 1, L.sub.1, L.sub.2 and L.sub.3 are each independently a non-labile linker [NLL] or a labile linker [LL} or a combination of one or more non-labile linkers and labile linkers wherein said non-labile linker [NLL] is a (poly)ethylene glycol or polyethylene-co-polypropylene linker ranging in length from 2 to about 100 ethylene glycol units; a group according to the chemical structure: ##STR00085## where n and n' are each independently from 1 to 100; a group according to the structure: ##STR00086## Where Z and Z' are each independently a bond, --(CH.sub.2).sub.i--O, --(CH.sub.2).sub.i--S, --(CH.sub.2).sub.i--N--R, ##STR00087## wherein said --(CH.sub.2).sub.i group, if present in Z or Z', is bonded to a multifunctional connector [MULTICON], an optional difunctional connector [CON], [ABT], [CBT] or [TLR]; Each R is H, or a C.sub.1-C.sub.3 alkyl or alkanol group; Each R.sup.2 is independently H or a C.sub.1-C.sub.3 alkyl group; Each Y is independently a bond, O, S or N--R; Each i is independently 1 to 100; D is ##STR00088## or a bond, or D is ##STR00089## or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 glycol units; with the proviso that Z, Z' and D are not each simultaneously bonds; j is 1 to 100; m' is 1 to 100; n is 1 to 100; X.sup.1 is O, S or N--R; R is as described above; R.sub.a is H, C.sub.1-C.sub.3 alkyl or alkanol or forms a cyclic ring with R.sup.3 (proline) or R.sup.3 is a side chain derived from an amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R.sup.3 forms a cyclic ring with R.sub.a and the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl); m'' is an integer from 1 to 25; m is an integer from about 1 to 100; and n is an integer from about 1 to 100, or a group according to the chemical structure: ##STR00090## where each X.sup.S is independently S, O or N--R.sup.S, preferably S; R.sup.S is H or C.sub.1-3 alkyl, preferably H; S.sub.c is CH.sub.2; CH.sub.2O; or CH.sub.2CH.sub.2O; i is 0 or 1; and m.sup.S is 0, 1, 2, 3, 4, 5, or 6, and said labile linker [LL] is a group according to the chemical structure: ##STR00091## ##STR00092## where R is an ethylene glycol group or a methylene group; n is from 0 to 10; X is O, N--R.sup.AL or S; R.sup.AL is H or a C.sub.1-C.sub.3 alkyl group; Y is O or S and Z=Me, Et, iPr, tBu, Ph, each of which may be optionally substituted with one or more halogen groups and wherein said Ph group may be further optionally substituted with a C.sub.1-C.sub.3 alkyl group which may be optionally substituted with up to three halogens or OMe; or [LL] is a group according to the chemical formula: ##STR00093## and R is an ethylene glycol group, or a methylene group; and n is from 0 to 10; or [LL] is an enzymatically cleaved labile linker according to the chemical structure: ##STR00094## Where the protease (cathepsin) substrate is a peptide substrate of protease containing from 2 to 50 amino acid units; where R is an ethylene glycol group, or a methylene group; and n is from 0 to 10; or [LL] is a group according to the chemical structure: ##STR00095## Where the points of attachment in each of the labile linkers as indicated above are covalently attached to other portions of the labile linker, a multifunctional connector moiety [MULTICON], an optional connector moiety (CON), a non-labile linker (NLL), an [ABT] group, a [CBT] group or a [TLR] group; And [MULTICON] is the same as in claim 1. 3. The compound according to claim 2 wherein said protease substrate in said labile linker [LL] is -Gly-Phe-Leu-Gly-; -Ala-Leu-Ala-Leu; -Phe-Arg-; -Phe-Lys-; -Val-Cit-; -Val-Lys- or -Val-Ala-. 4. The compound according to claim 1 wherein [ABT] is ##STR00096## Where X is O or NH; Y' is H; X' is O; and Z is a bond, a monosaccharide or a disaccharide, or [ABT] is ##STR00097## Where X.sub.R is O or S; and X.sub.M is O or S. 5. The compound according to claim 1 wherein [ABT] is ##STR00098## Where X is O or NH; and X.sub.R iS O or S. 6. The compound according to claim 1 wherein [ABT] is ##STR00099## Where X is O or NH; X.sub.R is O or S; and X.sub.M is O or S. 7. The compound according to claim 1 wherein [ABT] is ##STR00100## Where X.sub.R is O or S; and X.sub.M is O or S. 8. The compound according to claim 4 wherein Z is a monosaccharide selected from the group consisting of aldoses, ketoses and aminosugars. 9. The compound according to claim 1 wherein said non-labile linker is a (poly)ethylene glycol or polyethylene-co-polypropylene linker ranging in length from 1 to about 100 ethylene glycol units. 10. The compound according to claim 9 wherein said non-labile linker is a (poly)ethylene glycol linker ranging in length from about 2 to about 10 ethylene glycol units. 11. The compound according to claim 1 wherein said non-labile linker is a linker according to the chemical structure ##STR00101## where n and n' are each independently from 1 to 100. 12. The compound according to claim 11 wherein n and n' in the linkers of claim 11 are each independently 2 to 10. 13. The compound according to claim 1 wherein said non-labile linker is a group according to the structure: ##STR00102## Where Z and Z' are each independently a bond, --(CH.sub.2).sub.i--O, --(CH.sub.2).sub.i--S, --(CH.sub.2).sub.i--N--R, ##STR00103## wherein said --(CH.sub.2).sub.i group, if present in Z or Z', is bonded to said multifunctional connector group [MULTICON], an optional difunctional connector group [CON], said [ABT] group, said [CBT] group or said [TLR] group; Each R is H, or a C.sub.1-C.sub.3 alkyl or alkanol group; Each R.sup.2 is independently H or a C.sub.1-C.sub.3 alkyl group; Each Y is independently a bond, O, S or N--R; Each i is independently 1 to 100; D is ##STR00104## or a bond, or D is ##STR00105## or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 glycol units; with the proviso that Z, Z' and D are not each simultaneously bonds; j is 1 to 100; m' is 1 to 100; n is 1 to 100; X.sup.1 is O, S or N--R; R is as described above; R.sub.a is H, C.sub.1-C.sub.3 alkyl or alkanol or forms a cyclic ring with R.sup.3 (proline) and R.sup.3 is a side chain derived from an amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline (R.sup.3 forms a cyclic ring with R.sub.a and the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl); m'' is an integer between 0 to 25; m is an integer from 1 to 100, or a group according to the chemical structure: ##STR00106## where each X.sup.S is independently S, O or N--R.sup.S; R.sup.S is H or C.sub.1-3 alkyl; S.sub.c is CH.sub.2; CH.sub.2O; or CH.sub.2CH.sub.2O; i is 0 or 1; and m.sup.S 0, 1, 2, 3, 4, 5, or 6. 14. The compound according to claim 1 wherein said non-labile linker [NLL] is a group according to the structure: ##STR00107## where R.sub.a is H, C.sub.1-C.sub.3 alkyl or alkanol or forms a cyclic ring with R.sup.3 (proline) and R.sup.3 is a side chain derived from an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline (R.sup.3 forms a cyclic ring with R.sub.a and the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine, threonine, tryptophan, tyrosine and valine; m'' is an integer from 1 to 10; and m is an integer from 1 to 100. 15. The compound according to claim 1 wherein said labile linker [LL] is a group according to the chemical structure: ##STR00108## ##STR00109## where R is an ethylene glycol group or a methylene group; n is from 1 to 10; X is O, N--R.sup.AL or S; R.sup.AL is H or a C.sub.1-C.sub.3 alkyl group; Y is O or S and Z=Me, Et, iPr, tBu, Ph, each of which may be optionally substituted with one or more halogen groups and wherein said Ph group may be further optionally substituted with a C.sub.1-C.sub.3 alkyl group which itself may be optionally substituted with up to three halogens or OMe; or [LL] is a group according to the chemical formula: ##STR00110## and Where R is an ethylene glycol group, or a methylene group; and n is from 1 to 10; or [LL] is an enzymatically cleavable labile linkers according to the chemical structure: ##STR00111## Where the protease (cathepsin) substrate is a peptide substrate of protease containing from 2 to 50 amino acid units; where R is an ethylene glycol group, or a methylene group; and n is from 0 to 10; or [LL] is a group according to the chemical structure: ##STR00112## Where the points of attachment in each of the labile linkers as indicated above are covalently attached to other portions of the labile linker, said multifunctional connector [MULTICON], an optional difunctional connector moiety (CON), a non-labile linker (NLL), said [ABT] group, said [CBT] group or said [TLR] group. 16. The compound according to claim 15 wherein said protease substrate is -Gly-Phe-Leu-Gly-; -Ala-Leu-Ala-Leu; -Phe-Arg-; -Phe-Lys-; -Val-Cit-; -Val-Lys- or -Val-Ala-. 17. The compound according to claim 1 wherein said linker is group according to the chemical formula: ##STR00113## Where R.sub.a is H or forms a cyclic ring with R.sup.3 and R.sup.3 is a side chain derived from an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline (R.sup.3 forms a cyclic ring with R.sub.a and the adjacent nitrogen group to form a pyrrolidine group), hydroxyproline, serine, threonine, tryptophan, tyrosine and valine; m is an integer from 1 to 45; and m'' is an integer from 1 to 10. 18. The compound according to claim 2 wherein said optional difunctional connector group [CON] is a ##STR00114## group. 19. The compound according to claim 1 wherein said linker is a group according to the formula: ##STR00115## Wherein m is an integer from 1 to 15. 20. A compound according to claim 1 wherein ABT is ##STR00116## Where X is O or NH; [CBT] is ##STR00117## Where k is 4; and [TLR] is ##STR00118## 21. A compound according to claim 20 wherein X is NH, L.sub.1 is an alkylene group of between 2 and 12 methylene units in length, L.sub.2 is a ##STR00119## group where m in L.sub.2 is 4, 5, 6, 7, 8, 9, 12, 11 or 12; and L.sub.3 is a ##STR00120## group which is linked to said [TLR] group through a keto group and m in L.sub.3 is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. 22. The compound according to claim 21 wherein L.sub.2 is a ##STR00121## group; m is 3, 4 5, 6, 7, 8, 9 or 10; and L.sub.2 is attached to CBT either directly or through [CON] and wherein [CON] is a triazole. 23. The compound as set forth in attached FIG. 4 according to the chemical structure: ##STR00122## or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 1 wherein L.sub.3 is a labile linker. 25. The compound according to claim 20 wherein L.sub.3 is a labile linker. 26. A pharmaceutical composition comprising an effective amount of a chimeric compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient. 27. The composition according to claim 26 wherein said composition further comprises an effective amount of an additional anticancer agent. 28. The composition according to claim 27 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or mixtures thereof. 29. The composition according to claim 27 wherein said agent is aldesleukin; aemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; aparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with poifeprosan 20 iplant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; dabepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; dnileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; domostanolone propionate; eliott's B soution; epirubicin; eoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; flgrastim; floxuridine (intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nfetumomab; LOddC; orelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof. 30. The composition according to claim 26 further comprising at least one antiandrogen compound. 31. The composition according to claim 26 further comprising at least one GNRh modulator. 32. The composition according to claim 26 further comprising at least one agent selected from the group consisting of flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, leuprolide, goserelin, triptorelin, buserelin, abiraterone acetate, sorafenib and mixtures thereof. 33. The composition according to claim 26 further comprising at least one agent selected from the group consisting of an enlarged prostate agent, eulexin, flutamide, goserelin, leuprolide, lupron, nilandron, nilutamide, zoladex and mixtures thereof. 34. The composition according to claim 26 in oral dosage form. 35. The composition according to claim 26 in parenteral dosage form. 36. The composition according to claim 35 wherein said parenteral dosage form is an intravenous dosage form. 37. The composition according to claim 26 in topical dosage form. 38. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a compound according to claim 1. 39. The method according to claim 38 wherein wherein said prostate cancer is metastatic prostate cancer. 40. A method of treating prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a composition according to claim 27. 41. A method of inhibiting metastasis of prostate cancer in a patient in need thereof comprising administering to said patient an effective amount of a compound according to claim 1 to said patient. 42. A method of treating cancer in a patient in need thereof comprising administering to said patient a composition according to claim 26. 43. The method according to claim 42 wherein said cancer is stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer or lymphoma. 44. A method of treating prostate cancer in a patient wherein said patient also has another form of cancer, said method comprising administering to said patient an effective amount of a composition according to claim 27. 45. The method according to claim 44 wherein said other form of cancer is stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer or lymphoma. 46. The method according to claim 44 wherein said other form of cancer is a carcinoma, a malignant melanoma, a myeloproliferative disease, a sarcoma, a tumor of the central nervous system, a germ-line tumor, a mixed type of neoplasia or a tumor of mixed origin.

Details for Patent 9,556,167

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Teknika Llc	TICE BCG	bcg live	For Injection	102821	06/21/1989		2021-05-01
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2021-05-01
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2021-05-01