USOO934,5766 B2 (12) United States Patent (10) Patent No.: US 9,345,766 B2 Zhang et al. (45) Date of Patent: *May 24, 2016 (54) COMBINATION THERAPIES COMPRISING (58) Field of Classification Search ANT-ERBB3 AGENTS USPC ..................................... 424/136.1:530/387.3 See application file for complete search history. (71) Applicant: Merrimack Pharmaceuticals, Inc., Cambridge, MA (US) (56) References Cited (72) Inventors: Bo Zhang, Lynnfield, MA (US); Charlotte McDonagh, Winchester, MA U.S. PATENT DOCUMENTS (US); Alexandra Huhalov, Cambridge, MA (US) 4.450,103 A 5/1984 Konrad et al. 4,588,585 A 5/1986 Market al. 4,704,692 A 11/1987 Ladner (73) Assignee: Merrimack Pharmaceuticals, Inc., 4,737.462 A 4, 1988 Market al. Cambridge, MA (US) 4,816,567 A 3/1989 Cabilly et al. 4.946,778 A 8, 1990 Ladner et al. (*) Notice: Subject to any disclaimer, the term of this $25 A 23: Mark et al patent is extended or adjusted under 35 5,132,405W-1 r. A 7, 1992 HustonustOn et al. 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A 6LX39/395 (2006.01) CR '7. 3.08: Primary Examiner — Yan Xiao A6 IK3I/565 (2006.015 (74) Attorney, Agent, or Firm — Clark & Elbing LLP A6 IK3I/38 (2006.01) A6 IK3I/496 (2006.01) A 6LX3/57 (2006.01) (57) ABSTRACT A6 IK33/24 (2006.01) Disclosed are methods and compositions for inhibiting the g 448 3. growth of a tumor (e.g., a malignant tumor) in a Subject. In A6 IK3I/337 30 6. 8: particular, combination therapies for treating a tumor in a A6 IK3I/436 (200 6,015 Subject by co-administering an agent selected from i) an A 6LX3/59 (2006.015 effective amount of an anti-estrogen agent; ii) an effective A6 IK3I/567 (2006.015 amount of a receptor tyrosine kinase inhibitor; iii) an effective C07K 6/28 (2006.01) amount of a MEK/PI3 kinase/AKT inhibitor; iv) an effective C07K 6/40 (2006.01) amount of MM-151; v) an effective amount of an mTOR A61 K39/00 (2006.01) inhibitor; and/or vi) an effective amount of trastuzumab or (52) U.S. Cl. TMD1, and/or combinations thereof, and an effective amount CPC ........... A61K.39/3955 (2013.01); A61K31/138 of a bispecific anti-ErbB2/anti-ErbB3 antibody. Also dis (2013.01); A61 K3I/337 (2013.01); A61 K closed is a bispecific anti-ErbB2/anti-ErbB3 antibody for use 3 1/4 196 (2013.01); A61 K31/436 (2013.01): in the therapy of a tumor in combination with an agent A6 IK3I/517 (2013.01); A61 K3I/519 selected fromi) an effective amount of an anti-estrogen agent; (2013.01); A61 K3I/565 (2013.01); A61 K ii) an effective amount of a receptor tyrosine kinase inhibitor; 3 1/567 (2013.01); A61 K3I/7068 (2013.01): iii) an effective amount of a MEK/PI3 kinase/AKT inhibitor; A61 K33/24 (2013.01); A61K 39/39558 iv) an effective amount of MM-151; v) an effective amount of (2013.01); A61K 45/06 (2013.01); C07K an mTOR inhibitor; and/or vi) an effective amount of trastu I6/2863 (2013.01); C07K 16/32 (2013.01); Zumab or TMD1, and/or combinations thereof. 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