Claims for Patent: 10,280,229

Summary for Patent: 10,280,229

Title:	Linkers and their application towards ADC
Abstract:	The present invention relates to linkers, containing amide surrogates with a regular or a novel lysosomal enzymatic cleavable dipeptidic unit, to connect cytotoxic drugs to antibodies. The present invention also relates to ADCs (antibody-drug conjugates) derived from these amide surrogate linkers for the treatment of cancers.
Inventor(s):	Li; Chun Sing (Shanghai, CN), Li; Jian (Shanghai, CN), Cang; Yong (Shanghai, CN), Chen; Shuhui (Shanghai, CN), Li; Gang (Shanghai, CN), Xu; Xiongbin (Shanghai, CN), Lu; Lun (Shanghai, CN)
Assignee:	MEDSHINE DISCOVERY INC. (Jiangsu, CN)
Application Number:	15/326,386
Patent Claims:	1. A linker of formula (I) to connect drugs to antibodies, ##STR00142## wherein, R is selected from the group consisting of CF.sub.2H, CF.sub.3, CF.sub.2CF.sub.3, and PhSO.sub.2Me; Q is selected from the group consisting of ##STR00143## L.sup.1 is selected from the group consisting of --(CR.sup.1R.sup.2).sub.m--(CR.sup.3R.sup.4)--(CR.sup.1R.sup.2).sub.n--, --(CR.sup.1R.sup.2).sub.m--(CR.sup.3R.sup.4)--O--(CR.sup.1R.sup.2).sub.n-- -, and --[(CR.sup.1R.sup.2)(CR.sup.1R.sup.2)X].sub.p--(CR.sup.1R.sup.2).su- b.q--; m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; p is 1, 2, 3, 4, 5, or 6; q is 1 or 2; R.sup.1 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; R.sup.2 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; R.sup.3 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; R.sup.4 is selected from the group consisting of H, C.sub.1-3 alkyl, OH, NR.sup.5R.sup.6, CO.sub.2H, P(O)(OH).sub.2, and SO.sub.3H, said C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; R.sup.5 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; R.sup.6 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; X is selected from the group consisting of NR.sup.7, O, S(O).sub.r; r is 0, 1, or 2; R.sup.7 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; L.sup.2 is a di-peptide unit selected from ##STR00144## R.sup.8 is selected from the group consisting of methyl, propyl, isopropyl, sec-butyl, benzyl, and ##STR00145## R.sup.9 is selected from the group consisting of (CH.sub.2).sub.4NH.sub.2, (CH.sub.2).sub.3NHCONH.sub.2, (CH.sub.2).sub.3NHC(.dbd.NH)NH.sub.2, ##STR00146## s is 0, 1, 2, 3, or 4; L.sup.3 is a self-immolative unit selected from the group consisting of ##STR00147## R.sup.10 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; each R.sup.11 is independently selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; two geminal R.sup.11 may be optionally joined together to form a 3-6 membered ring with a carbon atom to which they are attached; two adjacent R.sup.11 may be optionally joined together to form a 5-7 membered ring with a carbon atom to which they are attached; R.sup.12 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2; and R.sup.13 is selected from the group consisting of H and C.sub.1-3 alkyl optionally substituted with 1, 2 or 3 of substituents independently selected from the group consisting of halogen, OH, NH.sub.2, NHMe, and NMe.sub.2. 2. A drug-linker conjugate of formula (II), ##STR00148## wherein, Q' is selected from the group consisting of ##STR00149## M is a drug; and other variables are as defined in claim 1. 3. An anti-drug conjugate (ADC) of formula (III) containing the linker of claim 1, ##STR00150## wherein, Y is an antibody; a is an integer or decimal selected from 1-8; M is a drug; and other variables are as defined in claim 1. 4. The linker of claim 1, wherein the antibody is selected from the group consisting of a resurfaced monoclonal antibody, a resurfaced single chain monoclonal antibody, or a resurfaced monoclonal antibody fragment; or the antibody is selected from the group consisting of a humanized monoclonal antibody, a humanized single chain monoclonal antibody, or a humanized monoclonal antibody fragment; or the antibody is selected from the group consisting of a chimeric antibody, a chimeric antibody fragment, a domain antibody, or a domain antibody fragment thereof; or the antibody is selected from the group consisting of MY9, anti-B4, EpCAM, CD2, CD3, CD4, CD5, CD6, CD11, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, EphA receptors, EphB receptors, EGFR, EGFRvIII, HER2, HER3, mesothelin, cripto, alpha.sub.vbeta.sub.3, alpha.sub.vbeta.sub.5, alpha.sub.vbeta.sub.6 integrin or C242; or the antibody is selected from the group consisting of My9-6, B4, C242, N901, DS6, EphA2 receptor, CD38, IGF-IR, CNTO 95, B-B4, Trastuzumab, Tertuzumab, Bevatuzumab, Sibrotuzumab, Rituximab, and Adalimumab; or the antibody is selected from the group consisting of Herceptin and Erbitux. 5. The linker of claim 1, wherein the antibody 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, MUCI, MUCI 6, 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, CD70, CD79, CD105, CD138, EphA receptors, EphB receptors, EGFRvIII, HER2/neu, HER3, mesothelin, cripto, alpha.sub.vbeta.sub.3 integrin, alpha.sub.vbeta.sub.5 integrin, alpha.sub.vbeta.sub.6integrin, Apo2, and C242 antigens; or cells expressing insulin growth factor receptor, epidermal growth factor receptor, and folate receptor. 6. The linker of claim 1, wherein the drug is a cytotoxic drug, or the drug is a diagnostic or detection reagent. 7. The linker of claim 1, wherein L.sup.1 is selected from the group consisting of: ##STR00151## 8. The linker of claim 1, wherein L.sup.2 is selected from the group consisting of ##STR00152## 9. The linker of claim 1, wherein the ring formed by two geminal R.sup.11 or two adjacent R.sup.11 is cyclohexyl. 10. The linker of claim 1, wherein L.sup.3 is selected from the group consisting of ##STR00153## 11. The linker of claim 1, wherein the moiety of ##STR00154## is selected from the group consisting of ##STR00155## 12. The linker of claim 1, wherein the linker is selected from the group consisting of ##STR00156## ##STR00157## 13. The drug-linker conjugate of claim 2, it is selected from the group consisting of ##STR00158## ##STR00159## 14. The ADC of claim 3, it is selected from the group consisting of ##STR00160## ##STR00161## Y is an antibody, a is an integer or decimal selected from 1-8. 15. A pharmaceutical composition comprising an effective amount of the ADC of claim 3 and a pharmaceutically acceptable carrier, diluent or excipient. 16. A process for treating a patient in need of a medicament for cancers, comprising administering to the patient a medicament comprising an effective amount of the linker in claim 1. 17. A process for treating or diagnosising a patient in need of a medicament for cancers, comprising administrating to the patient a medicament comprising an effective amount of the ADC of claim 3. 18. An intermediate compound for the synthesis of the drug-linker conjugate of formula (II) in claim 2, comprising: ##STR00162## 19. The linker of claim 5, 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. 20. The linker of claim 6, wherein the drug is selected from the group consisting of maytansinoid, DNA-binding drug and its analog, calicheamicin, doxorubicin and its analog, vinca alkaloid, cryptophycin, dolastatin, auristatin and analog thereof, tubulysin, epothilone, taxoid and siRNA; or the drug is a radio-labeled compound. 21. The linker of claim 20, wherein the DNA-binding drug is CC-1065; or the drug is labeled with .sup.3H, .sup.18F, .sup.11C, .sup.13N, .sup.15O, .sup.201Tl, .sup.32P, .sup.51Cr, .sup.67Ga, .sup.123I, .sup.125I, .sup.131I, .sup.132I, .sup.131Cs, .sup.113Xe, .sup.133Xe, .sup.169Yb,.sup.198Au, .sup.203Hg, .sup.99mTc, .sup.113mIn, .sup.133mIn, .sup.75Se, .sup.186Re, .sup.153Sm, and .sup.89Sr. 22. The drug-linker conjugate of claim 6, wherein M is selected from the group consisting of ##STR00163## 23. The linker of claim 8, wherein L.sup.2 is selected from the group consisting of ##STR00164## 24. The drug-linker conjugate of claim 2, the moiety of ##STR00165## is selected from the group consisting of ##STR00166## 25. The linker of claim 12, wherein the linker is selected from the group consisting of ##STR00167## ##STR00168## ##STR00169## 26. The drug-linker conjugate of claim 13, it is selected from the group consisting of ##STR00170## ##STR00171## ##STR00172## 27. The ADC of claim 14, it is selected from the group consisting of ##STR00173## ##STR00174## ##STR00175## wherein Y is an antibody, a is an integer or decimal selected from 1-8. 28. The ADC of claim 27, it is selected from the group consisting of ##STR00176## ##STR00177## wherein a is an integer or decimal selected from 2-6. 29. The ADC of claim 28, it is selected from the group consisting of ##STR00178## ##STR00179## ##STR00180## ##STR00181## wherein a is an integer or decimal selected from 2-6.

Details for Patent 10,280,229

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2034-07-16
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-07-16
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-07-16
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	12/31/2002		2034-07-16
Abbvie Inc.	HUMIRA	adalimumab	Injection	125057	02/21/2008		2034-07-16