US 20150290152A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0290152 A1 KELNER (43) Pub. Date: Oct. 15, 2015 (54) AFFINITY MEDICANT CONJUGATE (52) U.S. Cl. (71) Applicant: AF CHEMICALS, LLC CPC ........... A6 IK31/19 (2013.01); A61K 47/48.123 (2013.01); A61 K3I/I22 (2013.01); A61 K (72) Inventor: MICHAEL KELNER, LA JOLLA, CA 47/48384 (2013.01); A61K 47/48269 (2013.01) (US) (21) Appl. No.: 14/684,218 (22) Filed Apr. 10, 2015 In an embodiment of the invention, a composition for treating 1C p 9 a cell population comprises an Affinity Medicant Conjugate Related U.S. Application Data (AMC). The medicant moiety can be a toxin including an (60) Provisional application No. 61/978,195, filed on Apr. acylfulvene or a drug moiety. The affinity moiety can be an 10, 2014. antibody, a binding protein, a steroid, a lipid, a growth factor, Publication Classification a protein, a peptide or nonpeptidic. The affinity moiety can be covalently bound to the medicant via a linker. Novel linkers (51) Ek'.L/19 (2006.01) that can be directed to cysteine, arginine or lysine residues A6 IK3I/22 (2006.01) based on solution pH allow greater flexibility in preserving A6 IK 47/48 (2006.01) and/or generating specific epitopes in the AMC. Patent Application Publication Oct. 15, 2015 Sheet 1 of 71 US 2015/0290152 A1 Figure 1 AM—LU — MM 1100 1200 1300 1 OOO Patent Application Publication Oct. 15, 2015 Sheet 2 of 71 US 2015/0290152 A1 Figure 2A Figure 2B 2C Figure 2D Figure 2E 1. R R R3 R1 6 R3 2 R2 R4ORs R2 ...R5 . O O Figure 2F Figure 2G Patent Application Publication Oct. 15, 2015 Sheet 3 of 71 US 2015/0290152 A1 Fl gure 2H F gure 2I (I) (H) -(O R2 R;-( O R2 R 1. X-R 5 1 R4 R4 Ró ró O O Figure 2J RdS Figure 2N X /s R 1s R1 r/ R R4 Figure 20 III IIIRs III R RO RO O O Patent Application Publication Oct. 15, 2015 Sheet 4 of 71 US 2015/0290152 A1 Figure 2P R2 R-(N R7 R Figure 2R Patent Application Publication Oct. 15, 2015 Sheet 5 of 71 US 2015/0290152 A1 Figure 2S a R3 R-N Figure 2V 2 Patent Application Publication Oct. 15, 2015 Sheet 6 of 71 US 2015/0290152 A1 Figure 3A Ab —LU— MM 1110 12OO 1300 1 OO1 Patent Application Publication Oct. 15, 2015 Sheet 7 of 71 US 2015/0290152 A1 Figure 3B Gf —LU — MM 1120 12OO 1300 1 OO2 Patent Application Publication Oct. 15, 2015 Sheet 8 of 71 US 2015/0290152 A1 Figure 4 Tumor Cell line 2 hr. 4 8 h r Myeloid leukemias Yes Yes Breast CarcinomaS Yes Yes Epidermoid Yes Yes Ovarian Yes Yes Lung CarcinomaS Yes Yes PrOState Carcinomas Yes Yes B Cell leukemiaS NO Yes T Cell leukemias NO Yes Fibroblasts (normal) NO Yes Patent Application Publication Oct. 15, 2015 Sheet 9 of 71 US 2015/0290152 A1 Figure 5 Unique DNA Damage Profile Other Drugs UV Illudin S XP-A H H H XP-B O -- -- XP-C H H O XP-D O H H XP-E H H O XP-F H H H CS-A +/- -- ---- CS-B +/- H HH ERCC1 H H H ERCC5 -- -- -- Indicates novel mechanism of action versus other chemotherapeutic agents Patent Application Publication Oct. 15, 2015 Sheet 10 of 71 US 2015/0290152 A1 Figure 6 S.- : Cytarabine MTO oxostic T o:-- royen Time (days) Patent Application Publication Oct. 15, 2015 Sheet 11 of 71 US 2015/0290152 A1 Figure 7 Mechanism Resistance to Irofulven Gp170/MDR1 NO Gp180/MRP NO Topoisomerase I NO Topoisomerase II NO LRP(vault) NO Thiol Content NO DNA repair (?) NO Myc expression NO Bcl-2 expression NO BRCA Status NO p53 status NO p21 Status NO Patent Application Publication Oct. 15, 2015 Sheet 12 of 71 US 2015/0290152 A1 Patent Application Publication Oct. 15, 2015 Sheet 13 of 71 US 2015/0290152 A1 Patent Application Publication Oct. 15, 2015 Sheet 14 of 71 US 2015/0290152 A1 Figure 10A Figure 10B CC Figure 10C Patent Application Publication Oct. 15, 2015 Sheet 15 of 71 US 2015/0290152 A1 O Figure 11 A -l H O - Patent Application Publication Oct. 15, 2015 Sheet 16 of 71 US 2015/0290152 A1 Patent Application Publication Oct. 15, 2015 Sheet 17 of 71 US 2015/0290152 A1 Figure 13A O Patent Application Publication Oct. 15, 2015 Sheet 18 of 71 US 2015/0290152 A1 Figure 14A O O N Sv?.o/V O YY O O O O HGS N1 O O O Figures 14B 'vy. O O O v OM Y. S/N HN-NH O to Figure 14C Patent Application Publication Oct. 15, 2015 Sheet 19 of 71 US 2015/0290152 A1 Figure 15A R1 R2 X O S-F C R3 R4 Figure 15B R1 R-FS X No y R2 C R3 R4 Figure 15C R1 R2 X R3 C R Patent Application Publication Oct. 15, 2015 Sheet 20 of 71 US 2015/0290152 A1 Figure 16A Figure 16B O OH R7 O Oi-f 2. Figure 16C Figure 16D Patent Application Publication Oct. 15, 2015 Sheet 21 of 71 US 2015/0290152 A1 Figure 17A Figure 17B Figure 17C Patent Application Publication Oct. 15, 2015 Sheet 22 of 71 US 2015/0290152 A1 100 S-xoSox$xoS N & - S - $88.8s 0.1 |--AAAAAA&accoss 1. 10 100 1000 10000 Antibody (ug/mL) Figure 18 Patent Application Publication Oct. 15, 2015 Sheet 23 of 71 US 2015/0290152 A1 100 1910 . D CM O 1920 Q SN 7, 1930 -0 1940 10 1. 10 100 Antibody (ug/mL) Figure 19A Patent Application Publication Oct. 15, 2015 Sheet 24 of 71 US 2015/0290152 A1 10 FigureO 19B s D 2 1950 & 20 1955 1-1 100 200 300 Antibody (ug/mL) 100 s Figure 19C s CM) & 6 roo - Antibody (ug/mL) Patent Application Publication Oct. 15, 2015 Sheet 25 of 71 US 2015/0290152 A1 100 Figure 19D S5 O 100 200 300 Antibody (ug/mL) 100 Figure 19E . 1980 D s CM) S50 1985 100 200 300 Antibody (ug/mL) Patent Application Publication Oct. 15, 2015 Sheet 26 of 71 US 2015/0290152 A1 Figure 21 A Os-N- O O O Figure 21B O O HOt, O O -s- ) { O Q HO, O Figure 21C Patent Application Publication Oct. 15, 2015 Sheet 27 of 71 US 2015/0290152 A1 Figure 22A Figure 22C Figure 22D Patent Application Publication Oct. 15, 2015 Sheet 28 of 71 US 2015/0290152 A1 OH HOt, HO, O O FIGURE 20AA OO1) FIGURE 20AB (OO2) Br HOn , , O FIGURE 20AC (003) FIGURE 20AD (004) HOt, O FIGURE 20AE (005) FIGURE 20AF (006) os-os O HOt, O FIGURE 20AG (007) FIGURE 20AH (008) Patent Application Publication Oct. 15, 2015 Sheet 29 of 71 US 2015/0290152 A1 29 -2O HO, HOt, O O FIGURE 20A (OO9) FIGURE 20AJ O1O) 2O NO2 HO, HOt, O O FIGURE 20AK (011) FIGURE 20AL (O12) O FIGURE 20AM (013) FIGURE 20AN (014) OH OEt ACO1, HO, O O FIGURE 20AO (O15) FIGURE 20AP (016) Patent Application Publication Oct. 15, 2015 Sheet 30 of 71 US 2015/0290152 A1 O OfructOSe 'OH HO, O is O O FIGURE 20AO (O17) FIGURE 20AR (018) OH N-N --oh HOt, HO, O O FIGURE 20AS (O19) FIGURE 20AT (020) oséole OY-1SoH HO, HO1, O O FIGURE 20AU (O21) FIGURE 20AV (022) HO/, HOt, O O FIGURE 20AW (O23) FIGURE 20AX (024) Patent Application Publication Oct. 15, 2015 Sheet 31 of 71 US 2015/0290152 A1 S-N-CO2Me *C) HOt, HO, O O FIGURE 20AY (025) FIGURE 20AZ (O26) on-op O-I-Ph O O HOt, HO1, O O FIGURE 20BA (027) FIGURE 20BB (O28) SN-COH S-N-CO2Me HOn , HOt, O O S1)CO-Me FIGURE 20BC (029) FIGURE 20BD (030) S-N-CO2Me OH HO/ HOf, OH O yco Me O FIGURE 20BE (031) FIGURE 20BF (032) Patent Application Publication Oct. 15, 2015 Sheet 32 of 71 US 2015/0290152 A1 OAC K O O FIGURE 20BG (O33) FIGURE 20BH (034) \2N^) HO HOI, O O FIGURE 20B (O35) FIGURE 20BJ (O36) CO2H S - COH2 HO1, HOI , O O FIGURE 20BK (O37) FIGUREGU 20BLO (O38) OMe OEt OMe OEt HO1, HOt, O O FIGURE 20BM (O39) FIGURE 20BN (040) Patent Application Publication Oct. 15, 2015 Sheet 33 of 71 US 2015/0290152 A1 2Y-2O OH TESO1, O O FIGURE 20BO (O41) FIGURE 20BP (O42) OTES OTES O O FIGURE 20BO (043) FIGURE 20BR (O44) OAC HO, O FIGURE 20BT (O46) HO, FIGURE 20BV (O48) Patent Application Publication Oct. 15, 2015 Sheet 34 of 71 US 2015/0290152 A1 HOt, O FIGURE 20BW (O49) FIGURE 20BX (O5O) FIGURE 20BY (O51) FIGURE 20BZ (O52) os-No-N-Br HOt. O FIGURE 20OA (O53) CH - S O i-K)-oh OH S R O FIGURE 20OC (O55) FIGURE 20OD (O56) Patent Application Publication Oct. 15, 2015 Sheet 35 of 71 US 2015/0290152 A1 FIGURE 20OE (057 FIGURE 20OF (O58) O OH Ku OH FIGURE 20OG (O59) FIGURE 20OH O6O) HO1, OH O O FIGURE 20O (O61) FIGURE 20O (062) OH COOH sus NHAC HOt, OH O FIGURE25 20CK (O63) FIGURE 20OL (064) Patent Application Publication Oct. 15, 2015 Sheet 36 of 71 US 2015/0290152 A1 H OS N- 2 O OSN 2.