IP Library › Granted Patent US 12,258,399
Granted Patent B2
US 12,258,399 · App. 17/401,046 · Granted Mar 25, 2025

Methods for achieving therapeutically effective doses of anti-CD47 agents

Inventors: Stephen Willingham (Sunnyvale, CA); Maureen Howard (Los Altos Hills, CA); Jie Liu (Palo Alto, CA); Ravindra Majeti (Palo Alto, CA); Susan Sweeney Prohaska (Mountain View, CA); Anne Kathrin Volkmer (Duesseldorf, DE); Jens-Peter Volkmer (Menlo Park, CA); Irving L. Weissman (Stanford, CA)
Assignee: The Board of Trustees of the Leland Stanford Junior University
C07K16/2803A61K38/1774A61K39/3955C07K16/2896A61K38/1816A61K2039/505A61K2039/54A61K2039/545C07K2317/24C07K2317/33C07K2317/73C07K2317/76C07K2317/92C07K2319/30Y02A50/30
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,258,399
App. No.
17/401,046
Granted
Mar 25, 2025
Kind
B2
Abstract

Methods are provided for treating a subject with a therapeutic dose of anti-CD47 agent by administering a primer agent prior to administering a therapeutically effective dose of an anti-CD47 agent to the subject.

Claims (24)

1. A method for treating cancer in a human subject, the method comprising:

(a) administering a sub-therapeutic dose of from 0.1 mg/kg to 10 mg/kg of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα, wherein the sub-therapeutic dose is sufficient to increase production of reticulocytes; and

(b) administering a therapeutically effective dose of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα; wherein step (b) is performed in a range of from 5 to 9 days after beginning step (a), thereby treating the cancer.

2. The method of claim 1 , wherein the sub-therapeutic dose is from 1 mg/kg to 5 mg/kg.

3. The method of claim 1 , wherein the sub-therapeutic dose is from 1 mg/kg to 3 mg/kg.

4. The method of claim 1 , wherein for step (b) a series of therapeutically effective doses is administered.

5. The method of claim 4 , wherein the series of therapeutically effective doses is administered at a dose from 10 mg/kg to 40 mg/kg.

6. The method of claim 1 , wherein the anti-CD47 antibody comprises a variable heavy (VH) region containing the VH complementarity regions, CDR1, CDR2 and CDR3, respectively set forth in SEQ ID NO:6, 7 and 8; and a variable light (VL) region containing the VL complementary regions, CDR1, CDR2 and CDR3, respectively set forth in SEQ ID NO:9, 10 and 11.

7. A method for treating cancer in a human subject, the method comprising:

(a) administering a sub-therapeutic dose of 1 mg/kg of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα, wherein the sub-therapeutic dose is sufficient to increase production of reticulocytes; and

(b) administering a series of therapeutically effective doses of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα of escalating concentration at doses from 10 mg/kg to about 30 mg/kg; wherein step (b) is administered semi-weekly, starting 8 days after beginning step (a); and wherein the anti-CD47 antibody comprises a variable heavy (VH) region containing the VH complementarity regions, CDR1, CDR2 and CDR3, respectively set forth in SEQ ID NO:6, 7 and 8; and a variable light (VL) region containing the VL complementary regions, CDR1, CDR2 and CDR3, respectively set forth in SEQ ID NO:9, 10 and 11, thereby treating the cancer.

8. The method of claim 7 , wherein the cancer is a pre-malignant condition.

9. The method of claim 7 , wherein the cancer is a hematologic cancer.

10. The method of claim 9 , wherein the hematologic cancer is a leukemia.

11. The method of claim 10 , wherein the leukemia is acute myeloid leukemia (AML).

12. The method of claim 9 , wherein the hematologic cancer is a lymphoma.

13. A method for treating cancer in a human subject, the method comprising:

(a) administering a series of two sub-therapeutic dose of 1 mg/kg of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα, wherein the sub-therapeutic dose is sufficient to increase production of reticulocytes; and

(b) administering a series of therapeutically effective doses of an anti-CD47 antibody that blocks the interaction between CD47 and SIRPα of escalating concentration at doses from 10 mg/kg to about 30 mg/kg; wherein step (b) is administered semi-weekly, starting 8 days after beginning step (a); and wherein the anti-CD47 antibody comprises a variable heavy (VH) region containing the VH complementarity regions, CDR1, CDR2 and CDR3, respectively set forth in SEQ ID NO:6, 7 and 8; and a variable light (VL) region containing the VL complementary regions, CDR1, CDR2 and CDR3, respectively set forth in SEQ ID NO:9, 10 and 11.

14. The method of claim 13 , wherein the cancer is a pre-malignant condition.

15. The method of claim 13 , wherein the cancer is a hematologic cancer.

16. The method of claim 15 , wherein the hematologic cancer is a leukemia.

17. The method of claim 16 , wherein the leukemia is acute myeloid leukemia (AML).

18. The method of claim 13 , wherein the hematologic cancer is a lymphoma.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 12, 2021
From: WILLINGHAM, STEPHEN; HOWARD, MAUREEN; LIU, JIE; MAJETI, RAVINDRA; PROHASKA, SUSAN SWEENEY; VOLKMER, ANNE K.; VOLKMER, JENS-PETER; WEISSMAN, IRVING L.
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 058099/0229 →
Continuity (6)
Continuation 17102183 · Nov 23, 2020
Continuation 16375238 · Apr 4, 2019
Division 15423325 · Feb 2, 2017
Continuation 14769069
Provisional Application 61800102 · Mar 15, 2013
Related Publication 20210380689A1 · Dec 9, 2021
References Cited (52)
US 5922674A · Anagnostou et al. · 1999 [cited by applicant]
US 7531501B1 · Anagnostou et al. · 2009 [cited by applicant]
US 9045541B2 · Eckelman et al. · 2015 [cited by applicant]
US 9151760B2 · Weissman et al. · 2015 [cited by applicant]
US 9352037B2 · Van den Berg · 2016 [cited by applicant]
US 11518806B2 · Willingham et al. · 2022 [cited by applicant]
US 20040213792A1 · Clemmons et al. · 2004 [cited by applicant]
US 20070113297A1 · Yang et al. · 2007 [cited by applicant]
US 20100239578A1 · Danska et al. · 2010 [cited by applicant]
US 20100323949A1 · Lu et al. · 2010 [cited by applicant]
US 20120282174A1 · Weissman et al. · 2012 [cited by applicant]
US 20140140989A1 · Eckelman et al. · 2014 [cited by applicant]
WO WO2009091547 · 2009 [cited by applicant]
WO WO2009091601 · 2009 [cited by applicant]
WO WO2011143624 · 2011 [cited by applicant]
WO WO2013109752 · 2013 [cited by applicant]
WO WO2014123580 · 2014 [cited by applicant]
Adamson et al(1999) Predicting the hematopoietic response to recombinant human erythropoietin (Epoetin alfa) in the treatment of the anemia of cancer, Oncology (Basel), vol. 56, No. 1, Jan. 1999 (Jan. 1999), pp. 46-53. [cited by applicant]
Alinari et ai., “Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia”, Oncogene, 2007, pp. 3644-3653, 26, Nature Publishing Group, London, United Kingdom. [cited by applicant]
Amegen, Prescribing information: Epogen (epoetin alfa), [Retrieved online Jul. 16, 2018: «URL: https://pi.amgen.com/media/amgen/ . . . /pi . . . /epogen/epogen_pi_hcp_english.pdf»], updated Sep. 20, 2017, 40 Pages. [cited by applicant]
Burger et al., “Phase II Trial of Bevacizumab in Persistent or Recurrent Epithelial Ovarian Cancer or Primary Peritoneal Cancer: A Gynecologic Oncology Group Study”, Journal Of Clinical Oncology, Nov. 20, 2007, pp. 5165… [cited by applicant]
Chao et al., “Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate Non-Hodgkin ymphoma”, Cell, Sep. 3, 2010, pp. 699-713, vol. 142, Issue 5, Elsevier, New York City, NY. [cited by applicant]
Chen et al., “The update clinical research advancement of cancer and treatment related anemia”, Journal of Modern Oncology, Nov. 25, 2008, pp. 1995-1998, vol. 16, No. 11 (English Abstract is provided), Journal of Modern… [cited by applicant]
Clynes et al., “Inhibitory Fe receptors modulate in vivo cytoxicity against tumor targets”, Nature Medicine, Apr. 2000, pp. 443-446, vol. 6, No. 4, Nature Publishing Group, London, United Kingdom. [cited by applicant]
Curriculum Vitae Randolph Wall, Ph.D., Filed: Aug. 5, 2016, 9 pages. [cited by applicant]
Declaration of Randolph Wall, Ph.D., Filed: Aug. 5, 2016, 107 Pages. [cited by applicant]
Del Mastro et al., “Randomized phase III trial evaluating the role of erythropoietin in the prevention of hemotherapy-induced anemia”, . J. Clin. Oncol., Jul. 1, 1997, pp. 2715-2721, 15, No. 7, American Society Clinical… [cited by applicant]
Engert, “Recombinant human erythropoietin in oncology: current status and further development”, Ann. Oncol, Oct. 2005, pp. 1584-1595, vol. 16, Issue 10, Oxford University Press, Oxford, United Kingdom. [cited by applicant]
Forty Seven, Inc., Petition For Inter Partes Review of U.S. Pat. No. 9,352,037, Filed: Aug. 5, 2016, Case No. PR2016-01529, 74 Pages. [cited by applicant]
Forty Seven, Inc., Petition For Inter Partes Review of U.S. Pat. No. 9,352,037, Filed: Aug. 8, 2016, Case No. PR2016-01530, 76 Pages. [cited by applicant]
Imai et al., “Comparing antibody and small-molecule therapies for cancer”, Nature Reviews/Cancer, Sep. 2006, pp. 714-727, vol. 6, Nature Publishing Group, London, United Kingdom. [cited by applicant]
Kasper C et al: “Recombinant human erythropoietin in the treatment of cancer-related anemia”. European Journal of Haematology. vol. 58. No. 4. 1997. pp. 251-256. [cited by applicant]
Kim et al., “Antibody Engineering for the Development of Therapeutic Antibodies”, Molecules and Cells, Aug. 18, 2005, pp. 17-29, vol. 20, No. 1, Korean Society for Molecular and Cellular Biology, Seoul, Korea. [cited by applicant]
Kim et al., “Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells”, Leukemia, May 30, 2012, pp. 2538-2545, 26(12), Springer Nature, Basingstoke, United Kingdom. [cited by applicant]
Liu et al., “Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential”, PLo One, Sep. 21, 2015, pp. 1-23, e0137345, 10(9), Plos One, San Francisco, CA. [cited by applicant]
Majeti et al., “CD47 is an adverse pronostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells”, Cell, Jul. 23, 2009, pp. 286-299, vol. 138, Issue 2, Elsevier, New York City, NY. [cited by applicant]
Mawby et al., “Isolation and characterization of CD47 glycoprotein: a multispanning membrane protein which is the same as integrin-associated protein (IAP) and the ovarian tumour marker OA3”, Biochem. J., 1994, pp. 525-… [cited by applicant]
Nowrousian et al. (1998) Recombinant human erythropoietin in the treatment of cancer-related or chemotherapy-induced anemia in patients with solid tumors. 11 Medical Oncology, vol. 15 Suppl 1, pp. S19-S28. [cited by applicant]
Musolino et al., Immunoglobulin G Fragment C Receptor Polymorphisms and Clinical Efficacy of Trastuzumab-Based Therapy in Patients With HER-2/neu-Positive Metastatic Breast Cancer, Journal Of Clinical Oncology, Apr. 10,… [cited by applicant]
Okazawa et al., “Negative Regulation of Phagocytosis in Macrophages by the CD47-SHPS-1 System”, The Journal Jf Immunology, 2005, pp. 2004-2011, 174, The American Association of Immunologists, Inc., Bethesda, MD. [cited by applicant]
Oldenborg, “Role of CD47 in Erythroid Cells and in Autoimmunity”, Leukemia & Lymphoma, 2004, pp. 319-1327, vol. 45, No. 7, Taylor and Francis, Abingdon United Kingdom. [cited by applicant]
Ozols, “Challenges for chemotherapy in ovarian cancer”, Annals of Oncology, May 2006, pp. v181-v187, vol. 7, Supplement 5, European Society for Medical Oncology, Lugano, Switzerland. [cited by applicant]
Pietsch et al., “Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies” Blood Cancer Journal, Feb. 24, 2017, vol. 7, No. 2, pp. 1-8, 7(2), e536, Nature Publishing, London, United Kingdom. [cited by applicant]
Procirit and Epogen Labels, pp. 1-68, Retrieved online from<URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103234s51991bl.pdf>, Retrieved on 02/22/20201. [cited by applicant]
Szenajch et al ,“The role of erythropoietin and its receptor in growth, survival and therapeutic response of human Tumor cells”, BBA—Revives on Cancer, Aug. 1, 2010, pp. 82-95, Vo1| 806, No. 1, Elsevier Science, Amsterd… [cited by applicant]
The Jackson Laboratory, (2021) , pp. 1-2, NOD.Cg-Prkdc<scid> 112rg<tm1Wji>/SzJ, [retrieved online from <URL:https://www.jax.org/ jax-mice-and-services/strain-data-sheet-pages/body-weight-chart-005557> Retrieved on Feb. … [cited by applicant]
Tibes et al., “Activity of Alemtuzumab in Patients with CD52-Positive Acute Leukemia”, Cancer, Jun. 15, 2006, pp. 2645-2651, vol. 106, No. 12, American Cancer Society, Atlanta, GA. [cited by applicant]
Vectibix Prescribing Information, pp. 1-14, Retrieved online from <URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 125147s0801bl.pdf>, Retrieved on Feb. 22, 2021. [cited by applicant]
Veillette et al., “High Expression of Inhibitory Receptor SHPS-1 and Its Association with Protein-tyrosine Phosphatase SHP-1 in Macrophages”, The Journal of Biological Chemistry, Aug. 28, 1998, pp. 22719-22728, vol. 273… [cited by applicant]
Weiskopf et al. (2013) “SIR alpha Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies” Science, vol. 341. No. 6141, pp. 88-91. [cited by applicant]
Willingham et al., “The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors”, Proc. Natl. Acad. Sci. USA, Apr. 24, 2012, pp. 6662-6667, 109 (17), National Academy of S… [cited by applicant]
Zheng et al., “Gene expression profiling of CD34p cells identifies a molecular signature of chronic myeloid leukemia blast crisis”, Leukemia, Apr. 13, 2006, pp. 1028-1034, 20, Nature Publishing Group, London, United Kin… [cited by applicant]