US 20140099254A1 US 20140099254A1 (19) United States (12) Patent Application Publication oo) Pub. No.: US 2014/0099254 A l Chang et al. (43 ) Pub. Date: A pr. 10,2014 (54) COMBINATION THERAPY FOR INDUCING A 61K 4S/06 (2006.01) IMMUNE RESPONSE TO DISEASE A61K 39/395 (2006.01) (52) U.S. Cl. (71) Applicant: IBC Pharmaceuticals, Inc., Morris CPC A 6 1 K 38/212 (2013.01); A61K39/3955 Plains, NJ (US) (2013.01); A61K39/39558 (2013.01); A61K 47/48569 (2013.01); A61K47/4853 (2013.01); (72) Inventors: Chien-Hsing Chang, Downingtown, PA A 6 1 K 45/06 (2013.01) (US); David M. Goldenberg, Mendham, USPC ... 424/1.11; 424/85.7; 424/142.1; 424/136.1; NJ (US); Edmund A. Rossi, Woodland 424/85.6; 424/85.5; 424/85.2 Park, NJ (US); Diane Rossi, Woodland Park, NJ (US) (57) ABSTRACT (73) Assignee: IBC Pharmaceuticals, Inc., Morris Plains, NJ (US) The present invention concerns combinations of two or more (21) Appl. No.: 14/106,737 agents for inducing an immune response to cancer or infec­ tious disease. Agents may include leukocyte redirecting com­ (22) Filed: Dec. 14, 2013 plexes, antibody-drug conjugates, interferons (preferably Related U.S. Application Data interferon-α), and/or checkpoint inhibitor antibodies. The leukocyte redirecting complexes have at least one binding site (63) Continuation-in-part of application No. 13/966,450, for a leukocyte antigen and at least one binding site for an filed on Aug. 14, 2013. antigen on a diseased cell or pathogen. Preferably, the com­ (60) Provisional application No. 61/807,998, filed on Apr. plex is a DNL™ complex. More preferably, the complex 3, 2013, provisional application No. 61/733,268, filed comprises a bispecific antibody (bsAb). Most preferably, the on Dec. 4, 2012, provisional application No. 61/682, bsAb is an anti-CD3xanti-CD19 bispecific antibody, 965, filed on Aug. 14, 2012. although antibodies against other leukocyte antigens and/or disease-associated antigens may be used. The complex is Publication Classification capable of targeting effector T cells, NK cells, monocytes or neutrophils to induce leukocyte-mediated cytotoxicity of (51) Int. Cl. cells associated with cancer or infectious disease. The cyto­ A 61K 38/21 (2006.01) toxic immune response is enhanced by co-administration of A 61K 47/48 (2006.01) interferon, checkpoint inhibitor antibody and/or ADC. hA19-Fab-DDD2 DDD AD2 Okt3scFv-AD2 PatentApplication Publication Apr. 10, 2014 Sheet I of 24 US 2014/0099254 Al F i a i hA19-Fab-DDD2 DDD AD2 Okt3scFv-AD2 PatentApplication PatentApplication Publication Apr. 10, 2014 Sheet 2 of 24 US 2014/0099254 A l FIG. 2 Daudi + T cells + 1 pg/mL (19)-3s Daudi + T cells = 100 24.2% ■ 45.6% 60.8% 2.16% TJ 60 Q3 2.97% 5.00% TniTfrm T - T 11Tn 10 10 10 10' 10 ' 10' 10” FL1-H:: CD20FriC FL1-H:: CD20 FITC PatentApplication Publication Apr. 10, 2014 Sheet 3 of 24 US 2014/0099254 Al I m PatentApplication Publication Apr. 10, 2014 Sheet 4 of 24 US 2014/0099254 A l σ> 'l O CO O OiIi-DSOO "H-Hd O lld-Dsao =H-Hd O OiU-Oiao=H-HJ o iid -οεαο =H-Hd FIG. FIG. 4 FL2-H= CD3 FL2-H= PE Oiu-Iieao=H-nd o j d i i i a o =H-Hd (19)-3s-mediated cell-to-cell association of Daudi and Jurkat aw-ctc? wu O lld-D sao =H-Hd PatentApplication PatentApplication Publication Apr. 10, 2014 Sheet 5 of 24 US 2014/0099254 A l FIG. 5 Comparison of DART and BITE cell-cell association vs. (19)-3s cell-cell association using Daudi B lymphocytes and Jurkat T cells (A) (B) Daudi (CD20-FITC) + Jurkat (CD3-PE) + (19)-3s 30-I Jurket T-Oille (CD3/TCWPKH26) + DmidI B-CClIs (CD19/CFSE) a 2 5 - -·- CD19xC03 DAHT • i t CDtQxTCR DART « 15- -Cl· CD19xCD3 BfTE (19)-3s -β* COISmAB > 1 0 * ■Φ* *420xTCR DART % (C ρο·Μν·ο«β· % CL Q- Q* ft· ft* <S V concentration <ug/mL) ^ ^ Λ *Figure from Moore et al. B lood2011.117:4542-4551. Q· (¾' <0· ft· Ί>· concentration ^g/mL) PatentApplication Publication Apr. 10, 2014 Sheet 6 of 24 US 2014/0099254 A l §P Ό I m PatentApplication Publication Apr. 10, 2014 Sheet 7 of 24 US 2014/0099254 A l JD CO CO CD CD CD CD CD PatentApplication PatentApplication Publication Apr. 10, 2014 Sheet 8 of 24 US 2014/0099254 A l FIG. 8 (A) T cell activation: T cell proliferation in response to (19)-3s (19)-3s3nM 1.QxlOi IL-2/PHA (19)-3s 30 pM (14)-3s 3 nM Viable Viable CD7+ (14)-3s 30 pM Untreated 0 1 2 3 4 5 6 7 8 Day 1.2X105-! 1.0x10s- -*-(19)-3s 3 nM W IL2/PHA Φ B-Depleted IL2/PHA O 8.0x10"- + B-Depleted (19)-3s 30 pM Untreated Q 6.0x10" O Φ ■Ω 4.0x10"^ ■ (0 > 2.0x10"- Days PatentApplication PatentApplication Publication Apr. 10, 2014 Sheet 9 of 24 US 2014/0099254 A l (A) (19)-3s FIG. 9 V) -J ■ N aim-6 * Raji Nalm-6 I Ramos 100η λ Namalwa 75- * (19)-3s Donorl • (19)-3s Donor 2 -14 -13 -12 -11 -10 -9 •8 Log Concentration (nM) 50- z -*-(14)-3s Donor 1 (B) 25- ’/ -*-(14)-3s Donor 2 (14)-3s % Specific Lysis 100· in -15 -14 -13 -12 -11 -10 •9 -8 in >» Log Concentration (M) -I ■ Nalm-6 ______________ICso * Raji Donor 1 2 pM ' Ramos Donor 2 6 pM δ Namalwa -14 -13 -12 -11 -10 -9 -8 Log Concentration (nM) PatentApplication Publication Apr. 10, 2014 Sheet 10 of 24 US 2014/0099254 A l FIG. FIG. IOA sjsAi oijpeds % PatentApplication Publication Apr. 10, 2014 Sheet 11 of 24 US 2014/0099254 A l to O CO O LO 00 σ> Έ CL C Q. O O CO CM ¢/) W ω CO CO I CO I I σ Γ CNs o ' O CM ■—^ ^ ■ -4 ► OO C 0 FIG. FIG. IOB O I 1 O C Φ O Φ C O O CO sisA-| ouiaeds % PatentApplication PatentApplication Publication Apr. 10, 2014 Sheet 12 of 24 US 2014/0099254 A l FIG. IOC Daudi 100- 90* (Λ 80* » 70- 60- (22)-3s 5 60 O k. (19)-3s i d 6 60 ■ ■H 50- τ O (20)-3s 0.3 89 φ 40- O. CO 30- 20 - 10- 0 - —Γ“ “Ι- Τ" “I -12 -11 ΊΟ -9 -8 Log Concentration (M) PatentApplication Publication Apr. 10, 2014 Sheet 13 of 24 US 2014/0099254 A l FIG. 11 (A) LS174T . £ 2 lo o - ] Φ > * 80- (14)-3s O 60- (19)-3s O 40 Φ Cl ( Ο 20 1 i 1-------1-------1-------1-------1-------1 6 -15 -14 -13 -12 -11 -10 -9 -8 Log Concentration (M) IC50 = 2 pM (B) Capan-1 CO 100-1 (/) > * 80- -J O 60- M— (E1)-3s 40- O (19)-3s Φ Ω. 20- CO 0- SO 1 1 1 1 1 1 1 1 O x 5 -14 -13 -12 -11 -10 -9 -8 -7 Log Concentration (M) IC50 = 29 pM PatentApplication Publication Apr. 10, 2014 Sheet 14 of 24 US 2014/0099254 A l FIG. IlC NCI-N87 110- 100- 90- 80- 70- (E1)-3s (15)-3s 60- (19)-3s 50- 40- 30- - % % Specific Lysis 20 10- -15 -14 -13 -12 -11 -10 -9 8 Log Concentration (M) PatentApplication Publication Apr. 10, 2014 Sheet 15 of 24 US 2014/0099254 A l FIG. 12 Expression* IC50 Max lysis (%) (pM) (20)-3s CD20 Daudi I <0.3 -90 (19)-3s CD19 Daudi I I -60 (22)-3s CD22 Daudi I ~5 -60 (20)-3s CD20 Nalmawa 0.11 30 53 (19)-3s CD19 Namalwa 1.67 63 60 (22)-3s CD22 Namalwa 0.06 ND 42 (20)-3s CD20 Jeko-I 1.02 I 90 (19)-3s CD19 Jeko-I 1.93 3000 50 (20)-3s CD20 Ramos TBD TBD TBD (19)-3s CD19 Ramos 0.84 0.17 79 (20)-3s CD20 Nalm6 TBD TBD TBD (19)-3s CD19 Nalm6 0.75 6 -93 (20)-3s CD20 Raji TBD TBD TBD (19)-3s CD19 Raji 2.55 >3000 41 (C2)-3s Daudi Jeko-I 20 88 PatentApplication Publication Apr. 10, 2014 Sheet 16 of 24 US 2014/0099254 A l s “ CD . to CM LO ΰθ IO =L M <0 . CO VO MCO O PQ O O O M Q uid ) aiunjOA Joum x Q u i d ) a u i n i o ^ y ^ ο π ι η χ I * CO . h- r^. _ h- CO O -¾ to £ IO O CM . IO CO . CO CM " CM O PatentApplication Publication Apr. 10, 2014 Sheet 17 of 24 US 2014/0099254 A l Time Time (Days) ZtmS 'W''u TjT TTT TTT TjT (£iu:>) diuii |OA Jouinx -S > *in Su TInie TInie (Days) FIG. FIG. 14 !ft In In !ft -d -2 I ■a Q I <u . CO I Time (Days) ( u ia ) a m n [0 A J o u i n x PatentApplication Publication Apr. 10, 2014 Sheet 18 of 24 US 2014/0099254 A l Gfi & O S Quia) OiuniOA .ιοιπηχ g Quia) amnion.-«οιηηχ ■ CO CO jj» £3 Φ CS m O £ Cfi O -½ «3 < IO I a “ S 1S S o PO ° CM H ° Pm O O cm ^ Quia) auinpA Jouinx Q Quia) auinioA Jouinx PatentApplication Publication Apr. 10, 2014 Sheet 19 of 24 US 2014/0099254 A l FIG. 16 (A) Therapeutic Efficacy of (El)-3s plus El*-2b T-CeIl Retargeting in Capan-I Tumor-Bearing Mice Untreated Control (El)-3s (47 μ&) El*-2b (2.5 μg) +1 0.75- (El)-3s + El*2b 0.50- S 0.25- 0.00 0 7 14 21 28 35 42 49 56 63 70 77 Time (Days) (B) Therapeutic Efficacy of (El)-3s plus PEGASYS T-Cell Retargeting in Capan-I Tumor-Bearing Mice -Untreated Control 1.