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( 12 ) United States Patent US010624968B2 (12 ) United States Patent (10 ) Patent No.: US 10,624,968 B2 Bennett et al. (45 ) Date of Patent : Apr. 21 , 2020 ( 54 ) COMPOUNDS FOR TREATING CANCER WO 2005113554 12/2005 WO 2006078161 7/2006 WO 2006078846 7/2006 (71 ) Applicant: Bicycle Therapeutics Limited , WO 2006122806 11/2006 Cambridge (GB ) WO 2007016176 2/2007 WO 2007044729 4/2007 ( 72 ) Inventors : Gavin Bennett , Cambridge (GB ) ; WO 2007053452 5/2007 Daniel Paul Teufel , Cambridge (GB ) WO 2007070514 6/2007 WO 2007084786 7/2007 WO 2007129161 11/2007 ( 73 ) Assignee : BICYCLERD LIMITED , Cambridge WO 2008039218 4/2008 (GB ) WO 2008109943 9/2008 WO 2008118802 10/2008 ( * ) Notice : Subject to any disclaimer, the term of this WO 2009098450 8/2009 patent is extended or adjusted under 35 WO 2009114512 9/2009 WO 2010089115 8/2010 U.S.C. 154 ( b ) by 0 days . WO 2011090760 7/2011 WO 2013050615 4/2013 (21 ) Appl. No.: 15 /862,964 WO 2016067035 5/2016 WO 2017191460 11/2017 ( 22 ) Filed : Jan. 5 , 2018 WO 2018127699 7/2018 (65 ) Prior Publication Data OTHER PUBLICATIONS US 2018/0200378 A1 Jul. 19 , 2018 Paul Polakis . Antibody Drug Conjugates for Cancer Therapy. Pharmacol Rev. Jan 1 , 2016 ;68 ( 1 ) :3-19 . ( Year: 2016 ) . * Related U.S. Application Data Heinis et al. Phage- encoded combinatorial chemical libraries based (60 ) Provisional application No. 62/ 443,508, filed on Jan. on bicyclic peptides . Nat Chem Biol, 2009 ; 5 ( 7 ) : 502-07. ( Year: 2009) . * 6 , 2017 Eder et al. A phage display derived stabilised bicyclic peptide (51 ) Int. Ci. targeting MMP- 14 shows high imaging contrast in small animal A61K 47/64 ( 2017.01 ) PET imaging. Eur J Nucl Med Mol Imaging (2015 ) 42 (Suppl A61P 35/00 ( 2006.01 ) 1 ) :S140 - OP337 . ( Year : 2015 ). * A61K 38/08 Berge et al. , “ Pharmaceutical Salts , ” Journal of Pharmaceutical ( 2019.01 ) Sciences , vol . 66 , No. 1 , Jan. 1977 (pp . 1-19 ) . CO7K 7764 ( 2006.01 ) ClinicalTrials.gov identified NCT02488759, “ An Investigational CO7K 7/50 ( 2006.01 ) Immuno - therapy Study to Investigate the Safety and Effectiveness (52 ) U.S. Cl. of Nivolumab , and Nivolumab Combination Therapy in Virus CPC A61K 47/64 (2017.08 ) ; A61K 38/08 associated Tumors (CheckMate358 ) ,” https://clinicaltrials.gov/ct2/ ( 2013.01 ) ; A61P 35/00 ( 2018.01 ); CO7K 7764 show / study/ NCT02488759 ( 7 pages ). ( 2013.01 ) ; CO7K 7/50 ( 2013.01 ) ClinicalTrials.gov identifier NCT02426892 , “ Nivolumab and HPV ( 58 ) Field of Classification Search 16 Vaccination in Patients with HPV - 16 Positive Incurable Solid CPC A61K 38/12 , A61K 47/64 ; A61K 38/00 ; Tumors , ” https://clinicaltrials.gov/ct2/show/study/NCT02426892 ( 8 C12N 2310/351 ; CO7K 16/2863 ; COOK pages ) 14/001 ; CO7K 7/64 ; CO7K 1/1072 ; COOK Okazaki et al. , “ A rheostat for immune responses : the unique 2319/70 properties of PD - 1 and their advantages for clinical application ,” See application file for complete search history . Nature Immunology, vol. 14 , No. 12, Dec. 2013 (pp . 1212-1218 ). Sounni et al ., “ MT1- MMP expression promotes tumor growth and ( 56 ) References Cited angiogenesis through an up -regulation of vascular endothelial growth factor expression , " FASEB Journal . vol. 16 , No. 6 , Apr. 2002 (pp . U.S. PATENT DOCUMENTS 555-564 ) . 6,552,065 B2 4/2003 Remiszewski et al . (Continued ) 7,390,799 B2 6/2008 Bruncko et al . 8,138,347 B2 3/2012 Adams et al. 8,906,682 B2 12/2014 June et al. Primary Examiner Marcela M Cordero Garcia 2013/0064791 A1 * 3/2013 Poelstra A61K 38/12 Assistant Examiner - Jia -Hai Lee 424 / 85.5 2013/0072598 Al * 3/2013 Yang COSH 1/06 (74 ) Attorney , Agent, or Firm Andrea L. C. Reid ; 524/10 Dechert LLP FOREIGN PATENT DOCUMENTS (57 ) ABSTRACT WO 2001042246 6/2001 WO 2002088112 11/2002 The present invention provides compounds, compositions WO 2003063794 8/2003 reof, and methods of using the same. WO 2004019973 3/2004 WO 2004077062 9/2004 WO 2004089925 10/2004 30 Claims, 17 Drawing Sheets WO 2004106328 12/2004 WO 2005007623 1/2005 Specification includes a Sequence Listing . US 10,624,968 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Zou et al ., “ PD -L1 (B7 -H1 ) and PD - 1 pathway blockade for cancer therapy : Mechanisms, response biomarkers , and combinations, " Science Translational Medicine , vol. 8 , No. 328 , Mar. 2016 (34 pages ). Guangzhi et al. , “ The influence of the penetrating peptide iRGD on the effect of paclitaxel- loaded MT1 -AF7p -conjugated nanoparticles on glioma cells ” , Biomaterials , vol. 34 , No. 21, 2013 , pp . 5138 5148 International Search Report for PCT/GB2018 /050017 . * cited by examiner U.S. Patent Apr. 21 , 2020 Sheet 1 of 17 US 10,624,968 B2 BT17BDC - 23 in human plasma t = >> 24 hrs 1/2 cremaining 96 % remaining after 6 hrs BT17BDC - 23 in mouse plasma t = 6.4 hrs 1/2 57 % remaining after 6 hrs 2 Figure 1 U.S. Patent Apr. 21 , 2020 Sheet 2 of 17 US 10,624,968 B2 BT17BDC - 23 mouse plasma ( 4 UM + S ) with and without AESBF inhibitor 20 Figure 2 U.S. Patent Apr. 21 , 2020 Sheet 3 of 17 US 10,624,968 B2 BDC23 and MMAE metabolites BDC23 , AEBSF 80 BDC23 , -AEBSF %buluewal free MMAE, -AEBSE 20 free MMAE , & AEBSF 15 20 30 time (hrs ] Col1 vs 1293 > 1203 BD023 with AESSF Figure 3 U.S. Patent Apr. 21 , 2020 Sheet 4 of 17 US 10,624,968 B2 2000 Vehicle the 1-1 0.1mg/ kg + 1-10.3mg/ kg + 1-1 1mg /kg 1500 1-1 3mg/ kg TumourVolume(mm”) 1000 500 0 2 6 8 10 12 14 A Days after start of dosing Figure 4 U.S. Patent Apr. 21 , 2020 Sheet 5 of 17 US 10,624,968 B2 2000 Vehicle + 1-1 1mg/ kg on thin 1-1 1mg/ kg + N241 1500 TumourVolume(mm”) H 1000 500 0 0 2 4 6 8 10 12 14 Days after start of dosing Figure 5 U.S. Patent Apr. 21 , 2020 Sheet 6 of 17 US 10,624,968 B2 3000 Vehicle , iv , biw E) . Docetaxel 20mpk , iv , qw 1-1 10mg/ kg 1-1 3mg/ kg 1-1 1mg/ kg 2000 TumourVolume(mm) 1000 0+ 0 20 40 60 A A A A ? ? ? ? ? Days after start of dosing Figure 6 U.S. Patent Apr. 21 , 2020 Sheet 7 of 17 US 10,624,968 B2 1500 motor Vehicle E ). Docetaxel 20mpk , iv , qw |-1 3mg/ kg 1-1 1mg/ kg 1000 A mm)Volume(Tumour H 500 --- 0 0 10 20 30 ? Days after start of dosing Figure 7 U.S. Patent Apr. 21, 2020 Sheet 8 of 17 US10,624,968 B2 26 ?? Vehicle , iV, biw 3. Docetaxel 20mpk, iv , qw 1-1 3mg/ kg 243 1-1 1mg/ kg weight(g)Body 22 1 20 .. Y 18 .....? ????? 16 0 10 20 30 A A ? A Days after start of dosing Figure 8 U.S. Patent Apr. 21, 2020 Sheet 9 of 17 US 10,624,968 B2 ? 1-3a , 10 mpk , biw 22 1-3a , 3 mpk, biw 1-3a , 1 mpk , biw 20 Vehicle 18 H 16 4 6 8 10 12 14 A A Days after start of dosing B 26 1-7 , 10 mpk , biw 24 1-7,3 mpk , biw Bodyweight(g) 1-7 , 1 mpk , biw 22 Vehicle 20 18 16 2 6 8 10 12 14 < Days after start of dosing ? 1-4a , 10 mpk , biw 22 1-4a , 3 mpk , biw Bodyweight(g) 1-4a , 1 mpk , biw 20 Vehicle 18 16 2 4 8 10 12 14 n Days after start of dosing D 26 1-8 , 10 mpk , biw 24 1-8 , 3 mpk , biw 1-8 , 1 mpk , biw Bodyweight(g) Vehicle 20 co 1 16 1 0 2 8 10 12 14 < A Days after start of dosing Figure 9 U.S. Patent Apr. 21 , 2020 Sheet 10 of 17 US 10,624,968 B2 A B 2500 , Vehicle 25009 Vehicle l - 3a , 1 mpk , biw 1-7 , 1 mpk , biw f- 3a , 3 mpk , biw 1-7,3 mpk , blu 20004 3-3a , 10 mpk , biw 2000 W 1-7, 10 mpk , biw TumourVolume)(mm 1500 TumourVolume(mm) 1500 1000 1000 500 H 0 2 4 HH 6 12 14 4 6 8 12 14 Days after start of dosing Days after start ofdosing ? 2500 2500 Vehicle Vehicle 1-4a , 1 mpk , biw 4-8 , 1 mpk , biw 1-42 , 3 mpk , biw 48 , 3 mpk , biw 2000 - 1-4a , 20 mpk , biw 2000 8-8 , 10 mpk , biw TumourVolume(mm) 1500 TumourVolume(mm) 1500 1000 1000 500-1 H 5004 it 2 4 6 8 14 4 6 8 12 14 Days after start of dosing Days after start of dosing Figure 10 U.S. Patent Apr. 21 , 2020 Sheet 11 of 17 US 10,624,968 B2 A 26 24 Bodyweight(g) 224 20 18 16 14- 0 2 4 6 8 10 12 14 Days after startA of dosing B 1400 Vehicle 1200 1-12 , 1 mp /kg , qw TumourVolume(mm) 1000 met tona 1-12 , 3 mp/ kg , qw 800 H 1-12 , 10 mp /kg , qw 600 400 200 0 0 2 6 8 10 12 Days after start of dosing Figure 11 U.S. Patent Apr. 21 , 2020 Sheet 12 of 17 US 10,624,968 B2 A 26 . 24 )Bodyweight(g 22 20 18 16+ 0 2 4 6 8 10 12 14 A Days after start of dosingA B 1400 Vehicle 1200 within 1-16 , 1 mp/ kg , biw 1000 patronicPoornana 1-16 , 3 mp /kg , biw TumourVolumemm)( 800 1-16 , 10 mp/ kg , biw 600 400 200 0 0 2 4 6 8 10 12 14 A ? Days after start of dosing Figure 12 U.S.
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