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EP-4735045-A2 - OXAZAPHOSPHORINE ANTIBODY DRUG CONJUGATES AND METHODS OF USE

EP4735045A2EP 4735045 A2EP4735045 A2EP 4735045A2EP-4735045-A2

Abstract

Disclosed herein are antibody-drug conjugates (ADCs) comprising an antibody conjugated via a linker to an oxazaphosphorine drug moiety and methods of using the antibody drug conjugates. Included are methods of treating undesirable or aberrant cell proliferation or hyperproliferative disorders, such as non-metastatic and metastatic neoplasia, cancer, stem cells and malignancies that express targets that bind to such antibodies, or fragments antibodies, antibody heavy and light chains or nanobodies.

Inventors

  • ALILA, HECTOR

Assignees

  • La Life Products, LLC

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A composition comprising an antibody-drug conjugate of the formula Ab-(L-D) n wherein Ab is an antibody, antibody fragment, antibody chain, affibody, aptamer, or a nanobody; D is an active oxazaphosphorine payload; L is a linker; and n has a value of 2 to 20.
  2. 2. The composition of claim 1, wherein n has a value of 2-8.
  3. 3. The composition of claim 1 wherein the antibody is trastuzumab.
  4. 4. The composition of claim 1 wherein the antibody is sacituzumab.
  5. 5. The composition of claim 1 wherein the linker and active oxazaphosphorine payload is RTX5007.
  6. 6. The composition of claim 1 wherein the antibody-drug conjugate is trastuzumab-RTX5007.
  7. 7. The composition of claim 1 wherein the antibody-drug conjugate is sacituzumab-RTX5007.
  8. 8. The composition of claim 1, wherein the Ab binds to a tumor-associated antigen from at least one of a group comprising HER2, HER3, VEGF-A, VEGFR-2, CSF-1R, PD-L1, CEACAM5 or CEACAM6, ROR1, CD20, CD19, CD22, CD30, CD33, CD133, CD38, CD39 CD25, CD47, CD52, CD56, CD70, CD73, CD74, CD79b, CD155, CD166, FGF-receptor, B7-H3, B7-H4, LIV1, PSMA, PSCA, MAGE-A4, EpCAM, IL1R, CCR8, CCR4, Claudin, APPL2, BCMA, EGFR, DLL3/4, SSX-2, Tissue Factor, folate receptor, mesothelin receptor, NaPi2b, 5T4, Nectin-4, Nectin-2 (CD112), c-MeT, Trop-2, LHRH (GnRH) receptor, gonadotropin (LH/hCG, FSH) receptor, prolactin receptor, claudins; survivin, STEAP1, Transferrin receptor 1, NRG1, EphB2, and Caveolin-1.
  9. 9. The composition of claim 1, wherein the oxazaphosphorine payload is cytotoxic to immunosuppressive T-regulatory cells.
  10. 10. The composition of claim 1, wherein the oxazaphosphorine payload is cytotoxic to a cancer cell.
  11. 11. The composition of claim 1, wherein the oxazaphosphorine payload is of the formula: wherein at least one of R3, R4, Rs, and Re is a CH2CH2Y; wherein Y is a halogen; and wherein the remaining R3, R4, Rs, and Re groups are a hydrogen or a lower alkyl group.
  12. 12. The composition of claim 11, wherein the halogen is Cl or Br.
  13. 13. The composition of claim 11, wherein the hydrogen in R3 and Rs are replaced with deuterium to form CD2CH2Y or methyl (CH3) to form CH3CH2Y.
  14. 14. The composition of claim 11, wherein the oxazaphosphorine payload is of a structure selected from the group consisting of wherein R is an alkyl chain; wherein X and Y are halogen leaving groups; wherein X is a halogen leaving group; and wherein D is deuterium.
  15. 15. The composition of claim 11, wherein the oxazaphosphorine payload is selected from 4-hydroxy cyclophosphamide, aldophosphamide, phosphoramide mustard, 3- hydroxypropanal, isophosphoramide mustard, 4-hydroxycyclophosphamide, 4- hydroperoxycyclophosphamide, 4-hydroxyifosfamide, 4-hydroperoxyifosfamide evofosfamide, mafosfamide, glufosfamide, or trifosfamide mustard.
  16. 16. The composition of claim 11, wherein the oxazaphosphorine payload is selected from an analog or derivative of 4-hydroxycyclophosphamide, aldophosphamide, phosphoramide mustard, 3-hydroxypropanal, isophosphoramide mustard, 4-hydroxycyclophosphamide, 4- hydroperoxycyclophosphamide, 4-hydroxyifosfamide, 4-hydroperoxyifosfamide evofosfamide, mafosfamide, glufosfamide, or trifosfamide mustard.
  17. 17. The composition of claim 16 wherein the payload is phosphoramide mustard.
  18. 18. The composition of claim 16, wherein the derivative of 4-hydroperoxyifosfamide is 4- hydroxyifosfamide.
  19. 19. The composition of claim 16, wherein the analog or derivative of 4-hydroperoxyifosfamide (4- HO-ifosfamide) is deuterated (d4-hydroxyifosfamide).
  20. 20. The composition of claim 16, wherein the 4-hydroperoxycyclophosphamide derivative is 4- hydroxy cyclophosphami de.

Description

OXAZAPHOSPHORINE ANTIBODY DRUG CONJUGATES AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/524,400, filed June 30, 2023, which is incorporated by reference herein in its entirety. FIELD [0002] The invention generally relates to cancer treatment. The invention specifically relates to antibody-drug conjugates (ADCs) for use in cancer immunotherapy. BACKGROUND [0003] Human epidermal growth factor receptor-2 (HERZ) is a well-established target across a variety of malignancies, for tumors with HERZ overexpression or amplification (e.g. breast cancer, gastric, colorectal, cervical, endometrial, bladder, esophagogastric, biliary tract carcinoma, salivary gland) and HERZ mutations (e.g. NSCLC and more than 20 other tumor types) Raghav KPS and Moasser MM, Clin Cancer Res. 2023 July 05; 29(13): 2351-2361. doi: 10.1158/1078-0432.CCR-22-0283. HERZ targeting antibodies and ADCs, most prominently trastuzumab, trastuzumab-deruxtecan (T-DXd) and Trastuzumab emtansine (T-DM1), are standards of care for HERZ breast and other tumor types and for HERZ mutant tumors e.g. non-small cell lung cancer (NSCLC). Despite the effectiveness of the ADCs, resistance still occurs in many patients. For example, resistance to T-DXd emerges and appears to be most commonly due to resistance to the topoisomerase inhibitor payload because the loss of HER2 expression occurs in only a minority of the resistant cases. Another approved ADC that uses a topoisomerase inhibitor is Sacituzumab govitecan that treats cancers such breast cancer, bladder cancer that overexpress trophoblast cell surface antigen 2 (TROP2). TROP2 is also expressed in a variety of malignancies e.g. cervical, colorectal, ovarian, prostate, thyroid, gastric, brain, esophageal, head and neck, pancreatic and endometrial cancers. Development of resistance to Sacituzumab govitecan also occurs in part due to resistance to the topoisomerase inhibitor payload. Therefore, there is a major unmet need for a HER2 and TR0P2-targeting ADCs that use an alternative agent as a payload. This invention describes using oxazaphosphorines as alternative potent drug payloads to produce novel ADCs. SUMMARY [0004] In one aspect, the subject matter described herein is directed to an antibody conjugated to an oxazaphosphorine drug via a linker having the formula: Ab-(L-D)n wherein, D is an oxazaphosphorine, covalently bound via a linker (L) to an antibody (Ab) or antibody fragment that binds to a tumor antigen, and n has a value of 2 to 20. [0005] Another aspect of the subject matter described herein is the antibody may be engineered to enhance its antitumor cytotoxicity. The antibody may also be designed to bind simultaneously to one or more antigens on the target cells. [0006] Another aspect of the subject matter described herein is an antibody fragment, nanobody, affibody or Heavy/Light chains. [0007] Another aspect of the subj ect matter described herein is an activated oxazaphosphorine selected from a group comprising an active metabolite, analog or derivative that has direct antitumor cytotoxicity (“tumoricidal activity”). [0008] Another aspect of the subj ect matter described herein is an activated oxazaphosphorine selected from a group comprising an active metabolite, analog or derivative that stimulates the antitumor immune system by depleting or reducing the number and/or inhibiting the function of immunosuppressive cells such as regulatory T cells (Tregs) in the tumor microenvironment (TME). [0009] Another aspect of the subject matter described herein is a pharmaceutical composition comprising an oxazaphosphorine antibody-drug conjugate, and one or more pharmaceutically acceptable excipients. [0010] Another aspect of the subject matter described herein is the use of an antibody - oxazaphosphorine drug conjugate in methods of treating patients by administering to a subject a pharmaceutical composition comprising the oxazaphosphorine-antibody conjugate. [0011] Another aspect of the subject matter described herein is a method of making an antibody-drug conjugate covalently linked to an oxazaphosphorine. [0012] Another aspect of the subject matter described herein is an article of manufacture comprising a pharmaceutical composition comprising an antibody or fragment conjugated to oxazaphosphorine, a container, and a package insert or label indicating that the pharmaceutical composition can be used to treat a patient. [0013] In one aspect, the subject matter described herein is directed to a composition comprising an antibody-drug conjugate of the formula Ab-(L-D)n wherein Ab is an antibody, antibody fragment, antibody chain, affibody, aptamer, or a nanobody; D is an active oxazaphosphorine payload; L is a linker; and n has a value of 2 to 20. [0014] In another aspect, n has a value of 2-8. [0015] In another aspect, the Ab binds to a tumor-associated antigen from at least one of a group compr