USOO9481732B2 (12) United States Patent (10) Patent No.: US 9.481,732 B2 Govindan et al. (45) Date of Patent: *Nov. 1, 2016 (54) DOSAGES OF IMMUNOCONJUGATES OF (2013.01); A61K 47/48715 (2013.01); A61 K ANTIBODIES AND SN-38 FOR IMPROVED 48/00 (2013.01); A61K 51/1045 (2013.01); EFFICACY AND DECREASED TOXCITY A61K 51/1093 (2013.01); A61N 5/00 (71) Applicant: Immunomedics, Inc., Morris Plains, NJ (2013.01); A61N 5/10 (2013.01); C07K 16/18 (US) (2013.01); C07K 16/2803 (2013.01); C07K 16/2833 (2013.01); C07K 16/2887 (2013.01); (72) Inventors: Serengulam V. Govindan, Summit, NJ C07K 16/30 (2013.01); C07K 16/303 (US); David M. Goldenberg, (2013.01); C07K 16/3015 (2013.01); C07K Mendham, NJ (US) 16/302.3 (2013.01); C07K 16/3061 (2013.01); (73) Assignee: Immunomedics, Inc., Morris Plains, NJ A6 IK 2039/505 (2013.01); A6 IK 2039/507 (US) (2013.01); A61 K 2039/545 (2013.01); C07K (*) Notice: Subject to any disclaimer, the term of this 231.6/96 (2013.01); C07K 2317/76 (2013.01); patent is extended or adjusted under 35 C07K 2317/92 (2013.01); C07K 2317/94 U.S.C. 154(b) by 0 days. (2013.01) (58) Field of Classification Search This patent is Subject to a terminal dis CPC ..... A61K 47/48: A61K 39/395; C07K 16/00 claimer. USPC ............. 424/1811, 178.1, 179.1; 530/391.9, (21) Appl. No.: 14/955,469 530/388.1 (22) Filed: Dec. 1, 2015 See application file for complete search history. (65) Prior Publication Data (56) References Cited US 2016/0090423 A1 Mar. 31, 2016 U.S. PATENT DOCUMENTS 4,036,945 A T. 1977 Haber Related U.S. Application Data 4,046,722 A 9, 1977 Rowland (62) Division of application No. 14/204,698, filed on Mar. (Continued) 11, 2014, now Pat. No. 9,226,973, which is a division of application No. 13/948,732, filed on Jul. 23, 2013, FOREIGN PATENT DOCUMENTS now Pat. No. 9,028,833. EP O2532O2 1, 1988 (60) Provisional application No. 61/736,684, filed on Dec. EP O306943 3, 1989 13, 2012, provisional application No. 61/749,548, (Continued) filed on Jan. 7, 2013. OTHER PUBLICATIONS (51) Int. Cl. A6 IK 47/48 (2006.01) US 6,558,648, 05/2003, Griffiths et al. (withdrawn) A 6LX 39/395 (2006.01) Bardia et al., “Therapy of refractory/relapsed metastatic triple negative breast cancer (TNBC) with an anti-Trop-2-SN-38 anti C07K 6/00 (2006.01) body-drug conjugate (ADC), SacituZumab govitecan (IMMU-132): C07K 6/30 (2006.01) Phase I/II clinical experience'. J. Clin Oncol 33, 2015 (suppl; abstr A6 IK3I/337 (2006.01) 1016), Retrieved from http://meetinglibrary.asco.org/content/ A6 IK 3/484 (2006.01) 150673-156. A6 IK 3/4375 (2006.01) Cardillo et al., "Sacituzumab Govitecan (IMMU-132), an Anti A6 IK3I/53 (2006.01) Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers'. Bioconjug A6 IK3I/675 (2006.01) Chem. May 20, 2015:26(5):919-31, Epub May 8, 2015. A6 IK3I/7088 (2006.01) Dang et al., "Hypoxia-inducible factor-1 target genes as indicators A6 IK3I/73 (2006.01) of tumor vessel response to vascular endothelial growth factor (Continued) inhibition’, Cancer Res. Mar. 15, 2008;68(6): 1872-80. (52) U.S. Cl. (Continued) CPC ......... C07K 16/3007 (2013.01); A61 K3I/337 Primary Examiner — Yan Xiao (2013.01); A61K 31/4184 (2013.01); A61 K (74) Attorney, Agent, or Firm — Richard A. Nakashima 31/4375 (2013.01); A61K 31/454 (2013.01); A6 IK3I/4745 (2013.01); A61K 3 1/513 (57) ABSTRACT The present invention relates to therapeutic immunoconju (2013.01); A61 K3I/675 (2013.01); A61 K gates comprising SN-38 attached to an antibody or antigen 31/7088 (2013.01); A61 K3I/713 (2013.01); binding antibody fragment. The antibody may bind to A61K 33/24 (2013.01); A61K 38/00 (2013.01); EGP-1 (TROP-2), CEACAM5, CEACAM6, CD74, CD19, A61K 38/14 (2013.01); A61K 38/19 (2013.01); CD20, CD22, CSAp, HLA-DR, AFP or MUC5ac and the A61K 39/3955 (2013.01); A61K 39/39533 immunoconjugate may be administered at a dosage of (2013.01); A61K 39/39558 (2013.01); A61 K between 4 mg/kg and 24 mg/kg, preferably 4, 6, 8, 9, 10, 12. 45/06 (2013.01); A61K 47/486 (2013.01); 16 or 18 mg/kg. When administered at specified dosages and A61K 47/4863 (2013.01); A61K 47/48384 schedules, the immunoconjugate can reduce Solid tumors in (2013.01); A61K 47/48561 (2013.01); A61 K size, reduce or eliminate metastases and is effective to treat 47/48569 (2013.01); A61K 47/48576 cancers resistant to standard therapies, such as radiation (2013.01); A61K 47/48584 (2013.01); A61 K therapy, chemotherapy or immunotherapy. 47/48592 (2013.01); A61K 47/48669 22 Claims, 9 Drawing Sheets US 9,481,732 B2 Page 2 (51) Int. Cl. 6,187,287 B1 2/2001 Leung et al. A6 IK 33/24 2006.O1 6,201,104 B1 3/2001 MacDonald et al. A6 IK 38/00 3. 6,214,345 B1 4/2001 Firestone et al. ( .01) 6,254,868 B1 7/2001 Leung et al. A6 IK 38/14 (2006.01) 6,306,393 B1 10/2001 Goldenberg A6 IK 38/19 (2006.01) 6,331,175 B1 12/2001 Goldenberg A6 IK 45/06 (2006.01) 6,379,698 B1 4/2002 Leamon 6,387,350 B2 5/2002 Goldenberg 1999 (2006.01)28.8 6,530,9446,395.276 B2B1 3/20035/2002 WestRybak et et al. al. A6IN 5/00 (2006.01) 6,562,318 B1 5/2003 Filler A6 IK 3L/454 (2006.01) 6,653,104 B2 11/2003 Goldenberg A6IN 5/10 (2006.01) 6,716,821 B2 4/2004 Zhao et al. C07K 6/28 (2006.01) 7,018,809 B1 3/2006 Carter 7,074,403 B1 7/2006 Goldenberg et al. A6 IK 3/4745 (2006.01) 7,122,636 B1 10/2006 Hsei et al. C07K 6/8 (2006.01) 7,151,164 B2 12/2006 Hansen et al. A61 K 39/00 (2006.01) 7,238,785 B2 7/2007 Govindan et al. 7.312,318 B2 12/2007 Hansen et al. 7,387,779 B2 6/2008 Kalluri (56) References Cited 7,585,491 B2 9/2009 Govindan et al. 7,591,994 B2 9, 2009 Govindan et al. U.S. PATENT DOCUMENTS 7,772,373 B2 8/2010 Hansen et al. 4,200,690 A 4, 1980 Root et al. 7,820,161 B1 10/2010 Curd et al. 7.910, 103 B2 3/2011 Goldenberg 4.331,647 A 5/1982 Goldenberg 7,931,903 B2 4/2011 Hansen et al. 4,359.457 A 11, 1982 Neville et al. 7.999,083 B2 8/2011 Govindan et al. 4,699,784. A 10/1987 Shih et al. 8,080,250 B1 12/2011 Govindan et al. 4,704,692 A 1 1/1987 Ladner 8,119,101 B2 2/2012 Byrd et al. 4,816,567 A 3/1989 Cabilly et al. 8,268.317 B2 9/2012 Govindan et al. 4,824,659 A 4, 1989 Hawthorne 8,268.319 B2 9/2012 Govindan et al. 4,916,213 A 4, 1990 Scannon et al. 8.420,086 B2 4/2013 Govindan et al. 4,918,163 A 4/1990 Young et al. 8.425,912 B2 4/2013 Govindan et al. 4,925,922 A 5/1990 Byers et al. 8,658,773 B2 2/2014 Zeng et al. 4,932,412 A 6/1990 Goldenberg 8,759.496 B2 6/2014 Govindan et al. 4.946,778 A 8, 1990 Ladner et al. 5,057,313 A 10, 1991 Shih et all 9,180.205 B2 11/2015 Zeng et al. W - h et al. 9,226,973 B2 * 1/2016 Govindan ............ A61K 31.454 5,106,955. A 4, 1992 Endo et al. 2001.0034363 A1 10, 2001 Li et al. 5, 112,954 A 5, 1992 Abrams et al. 2002/00 18749 A1 2/2002 Hudson et al. 5, 122,368 A 6, 1992 Greenfield et al. 2003/0103979 A1 6/2003 Leung et al. 5,134,075 A 7, 1992 Hellstrom et al. 2003. O133972 A1 7, 2003 Danthi et al. 5,171,665 A 12/1992 Hellstrom et al. 2004/0001838 A1 1/2004 Zhao et al. 3.33. A E Stal 2004/0076683 A1 4/2004 Hoarau et al. 5,229,2752.92. A 7/1993482 Goroillet al. 2006/01938652006/0142506 A1 8/20066/2006 GovindanBreitenkamp et al.et al. 5,443,953. A 3. Hair et al 2007/0212350 Al 9, 2007 Govindan et al. 3. A. E. E. 2008/O166363 A1 7/2008 Govindan et al. 5,525.338 A 6/1996 Goldenberg 2010, 0104589 A1 4/2010 Govindan et al. 5,565,215. A 10/1996 Gref et al. 2011/007015.6 A1 3f2011 Govindan et al. 5,567,610 A 10, 1996 Borrebaeck et al. 2011/0160 159 A1 6/2011 Ryan 5,593,676 A 1/1997 Bhat et al. 2011/0256053 Al 10/2011 Chang et al. 5,618,920 A 4/1997f AmkrRobinson et al.1 2011/0274704 Al 11/2011 Chang et al. 5,620,708 A $32 sal 2011/0305631 A1 12/2011 Govindan et al.