Claims for Patent: 8,613,930

Summary for Patent: 8,613,930

Title:	Cross-linkers and their uses
Abstract:	Charged or pro-charged cross-linking moieties and conjugates of cell binding agents and drugs comprising the charged or pro-charged cross-linking moieties and method of making the same.
Inventor(s):	Chari; Ravi V. J. (Newton, MA), Zhao; Robert Yongxin (Lexington, MA), Kovtun; Yelena (Stow, MA), Singh; Rajeeva (Framingham, MA), Widdison; Wayne Charles (Belmont, MA)
Assignee:	ImmunoGen, Inc. (Waltham, MA)
Application Number:	13/542,126
Patent Claims:	1. A cell-binding agent-drug conjugate of formula (II) ##STR00067## wherein: CB represents a cell-binding agent; D represents a cytotoxic drug linked to the cell-binding agent by a disulfide, thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amide bond; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a charged substituent selected from anions selected from SO.sub.3.sup.-, X--SO.sub.3.sup.-, OPO.sub.3.sup.2-, X--OPO.sub.3.sup.2-, PO.sub.3.sup.2-, X--PO.sub.3.sup.2-, and cations selected from a nitrogen containing heterocycle, N.sup.+R.sub.11R.sub.12R.sub.13 and X--N.sup.+R.sub.11R.sub.12R.sub.13, or a phenyl; wherein: R.sub.11, R.sub.12, and R.sub.13 are the same or different and are linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms; l, m and n are 0 or an integer from 1 to 4; Z is an optional polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is 0 or an integer from 2 to about 1000; Y represents a carbonyl, thioether, amide, disulfide, or hydrazone group; and q represents an integer from 1 to 20; wherein at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 is a charged substituent. 2. The conjugate of claim 1, wherein the cytotoxic drug is selected from thiotepa; cyclophosphamide; alkyl sulfonates selected from busulfan, improsulfan and piposulfan; aziridines selected from benzodopa, carboquone, meturedopa, and uredopa; ethylenimines; methylamelamines; acetogenins selected from bullatacin and bullatacinone; camptothecin; bryostatin; callystatin; CC-1065; adozelesin, carzelesin or bizelesin synthetic analogues of CC-1065; cryptophycins; dolastatin; duocarmycin; KW-2189 or CBI-TMI synthetic analogues of duocarmycin; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards selected from chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas selected from: carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics selected from: the enediyne antibiotics, calicheamicin, calicheamicin gammal and calicheamicin theta I; dynemicin, including dynemicin A; esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites selected from methotrexate and 5-fluorouracil (5-FU); folic acid analogues selected from denopterin, methotrexate, pteropterin, trimetrexate; purine analogs selected from fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimnidine analogs selected from ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens selected from calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals selected from: aminoglutethimide, mitotane, trilostane; folic acid replenisher selected from frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids selected from maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes selected from T-2 toxin, verracurin A, roridin A and anguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs selected from cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoic acid; capecitabine; anti-hormonal agents selected from anti-estrogens including tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens selected from flutamide, nilutamide, bicalutamide, leuprolide, and goserelin, siRNA or a combination thereof; and pharmaceutically acceptable salts, acids or derivatives of any of the above. 3. The conjugate of claim 1, wherein the cytotoxic drug is selected from maytansinoids, CC-1065 analogs, morpholino doxorubicin, taxanes, calicheamicins, auristatins, pyrrolobenzodiazepine dimmer, siRNA or a combination thereof, and pharmaceutically acceptable salts, acids or derivatives of any of the above. 4. The conjugate of claim 1, wherein the cell-binding agent binds to target cells selected from tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes, cells expressing one or more of IGF-IR, CanAg, EGFR, EphA2 receptor, MUC1, MUC16, VEGF, TF, MY9, anti-B4, EpCAM, CD2, CD3, CD4, CD5, CD6, CD11, CD11a, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, EphA receptors, EphB receptors, EGFr, EGFRvIII, HER2/neu, HER3, mesothelin, cripto, alpha.sub.vbeta.sub.3, integrin, alpha.sub.vbeta.sub.5 integrin, alpha.sub.vbeta.sub.6 integrin, Apo2, and C242 antigens; and cells expressing insulin growth factor receptor, epidermal growth factor receptor, or folate receptor. 5. The conjugate of claim 1, wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that binds the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, adnectins that mimic antibodies, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule. 6. The conjugate of claim 5, wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment thereof. 7. The conjugate of claim 5, wherein the antibody is a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof. 8. The conjugate of claim 5, wherein the antibody is a human antibody, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment thereof. 9. The conjugate of claim 5, wherein the antibody is a chimeric antibody, a chimeric antibody fragment, a domain antibody, or a domain antibody fragment thereof. 10. The conjugate of claim 8, wherein the antibody is My9-6, B4, C242, N901, DS6, EpCAM, EphA2 receptor, CD38, IGF-IR, CNTO 95, B-B4, trastuzumab, pertuzumab, bivatuzumab, sibrotuzumab, pertuzumab, or rituximab. 11. The conjugate of claim 4, wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, and testicular cancer cells. 12. A method of treating a tumor comprising administering to a subject in need of treatment a therapeutically effective amount of a conjugate of claim 1. 13. A compound of formula (III): ##STR00068## wherein: CB represents a cell-binding agent; Q represents a functional group that enables linkage of a cytotoxic drug via a disulfide, thioether, thioester, peptide, hydrazone, ester, ether, carbamate or amide bond; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a charged substituent selected from anions selected from SO.sub.3.sup.-, X--SO.sub.3.sup.-, OPO.sub.3.sup.2-, X--OPO.sub.3.sup.2-, PO.sub.3.sup.2-, X--PO.sub.3.sup.2-, and cations selected from a nitrogen containing heterocycle, N.sup.+R.sub.11R.sub.12R.sub.13 and X--N.sup.+R.sub.11R.sub.12R.sub.13, or a phenyl, wherein: R.sub.11, R.sub.12, and R.sub.13 are the same or different and are linear alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms; l, m and n are 0 or an integer from 1 to 4; Z is an optional polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is 0 or an integer from 2 to about 1000; and Y represents a carbonyl, thioether, amide, disulfide, or hydrazone group; and q represents an integer from 1 to 20; wherein at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 is a charged substituent. 14. A compound of formula (IV): ##STR00069## wherein: Y' represents a functional group that enables reaction with a cell-binding agent; D represents a cytotoxic drug linked to the cell-binding agent by a disulfide, thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amide bond; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a charged substituent selected from anions selected from SO.sub.3.sup.-, X--SO.sub.3.sup.-, OPO.sub.3.sup.2-, X--OPO.sub.3.sup.2-, PO.sub.3.sup.2-, X--PO.sub.3.sup.2-, and cations selected from a nitrogen containing heterocycle, N.sup.+R.sub.11R.sub.12R.sub.13 and X--N.sup.+R.sub.11R.sub.12R.sub.13, or a phenyl, wherein: R.sub.11, R.sub.12, and R.sub.13 are the same or different and are linear alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms; l, m and n are 0 or an integer from 1 to 4; Z is an optional polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is 0 or an integer from 2 to about 1000, wherein at least one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 is a charged substituent. 15. A pharmaceutical composition comprising an effective amount of the conjugate of claim 1, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 16. The conjugate of claim 1, wherein one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.9, and R.sub.10 is a charged substituent selected from SO.sub.3.sup.-, X--SO.sub.3.sup.-, OPO.sub.3.sup.2-, X--OPO.sub.3.sup.2-, N.sup.+R.sub.11R.sub.12R.sub.13 and X--N.sup.+R.sub.11R.sub.12R.sub.13, and the rest are H; l, g and m are each 0; and n is 1. 17. The conjugate of claim 16, wherein one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.9, and R.sub.10 is SO.sub.3.sup.- or X--SO.sub.3.sup.-, the rest are H; l, g and m are each 0; and n is 1. 18. The conjugate of claim 16, wherein Z is absent. 19. A cell-binding agent-drug conjugate represented by the following formula: ##STR00070## wherein D' is a cytotoxic drug, q represents an integer from 1 to 20, and CB'--represents a cell-binding agent. 20. The conjugate of claim 1, which is represented by one of the following formulae: ##STR00071## wherein D' is the cytotoxic drug, and CB'--NH-- represents the cell-binding agent linked to Y. 21. The conjugate of claim 20, which is represented by the following formula: ##STR00072## 22. The conjugate of claim 20, wherein the cytotoxic drug is a maytansinoid. 23. The conjugate of claim 20, wherein the cytotoxic drug is DM1 or DM4. 24. The conjugate of claim 21, wherein the cytotoxic drug is DM4. 25. The conjugate of claim 24, wherein the cell-binding agent is an antibody that binds to a folate receptor. 26. The conjugate of claim 25, wherein the folate receptor is FOLR1 (folate receptor 1).

Details for Patent 8,613,930

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2028-04-30
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2028-04-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2028-04-30