Anti-PTK7 conjugates and uses thereof
Patent Information
- Application Number
- AU2025259317
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-11-19
- Filing Date
- 2025-04-17
- Publication Date
- 2026-10-29
Smart Images
Figure 00000156_0000 
Figure 00000157_0000 
Figure 00000158_0000
Abstract
Description
I O cases, S4 is
[00234] In some embodiments, for a Linker or salt of Formula (III), or for a Drug-Linker or salt of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (I), Formula (I-A), Formula (la), Formula (LAAa), Formula (lb), Formula (I-AAb), Formula (LAA), Formula (I-B), Formula (II-A), Formula (II-B), Formula (II-C), Formula (II-D), or Formula (ILG), further includes attaching a Targeting Unit to M1 to form a conjugate, wherein M1 of the Drug-Linker reacts and forms a covalent bond to the Targeting Unit. In some cases, the Targeting unit is selected from an antibody or an antigen-binding portion thereof. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1 to 10. In some cases, the Targeting unit is selected from an antibody or an antigen-binding portion thereof. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1 to 8. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1 to 5. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10.
[00235] In some embodiments, for a conjugate or salt of Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII), Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-3), Formula (A-4), or Formula (A-7), M2 is a connector unit. In some cases, the connector unit refers to a component that connects different parts of the conjugate together. In some cases, the connector unit can connect the Targeting Unit to S3 (if present) or to S2. In some cases, the connector unit forms a bond with a sulfur atom of a Targeting unit. In some cases, the connector unit forms a bond with a sulfur atom of a Targeting unit via a maleimide group. In some cases, the sulfur atom can be derived from, for example, a sulfhydryl group of a Targeting / 0 unit (e.g., a thiol group of an interchain disulfide bond). In some cases, M2 is O . In / ^N 'N An'N''N CxA some cases, M2 is . In some cases, M2 is . In some cases, M2 is cases, M2 is -CH2-C(0)NH-. In some cases, M2 is linked to the Targeting unit via a disulfide bond between a sulfur atom of M2 and a sulfur atom of the Targeting unit. In some cases, M2 is I—s—I « «. In some cases, the connector unit forms a bond with a primary or secondary amino group of a Targeting unit. In some cases, M2 is selected from O , 0 , and
[00236] In an aspect, the present disclosure provides a Linker of Formula (III): R50 Formula (III) or a pharmaceutically acceptable salt thereof, wherein; n is selected from 0 and 1; m is selected from 0 and 1; wherein at least n or m is 1; p is selected from 0 and 1; X is selected from CH and N; Y is a -0-T1 and -NH-T2; T1 is a sugar cleavable unit; T2 is peptide cleavable unit; S1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(0)2- - S(O)2N(R20)- -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, —S(0)—, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)--S(0)2- or -P(O)(R20)2-; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)--S(0)2- or -P(O)(R20)2-; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S3 is selected from a spacer, wherein the spacer is preferably phenylene, wherein S3 is present or absent; S4 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; wherein the optional substituents on M1, K1, K2, S1, S2, S3, and S4, are independently selected at each occurrence from: (iv) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -o-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), and -CN; (ii) Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2,-N(R30)C(O)R30-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -0-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and (iii) C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, Ci-6 alkyl, C2.6 alkenyl, and C2-6 alkynyl; M1 is a group which can react with a ligand to form a connector unit; K1 is selected from: (iv) a peptide unit, (ii) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)--S(0)2- or-P(O)(R20)2-; (iii) an oligosaccharide; and (iv) a polyether; K2 is selected from: (iv) a peptide unit, (ii) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, - C(O)N(R20)-, -N(R20)S(O)2- - S(O)2N(R20)- -0- -C(O)-, -OC(O)-, -0(0)0-, -S-, -S(0)--S(0)2- or-P(O)(R20)2-; (iii) an oligosaccharide; and (iv) a polyether; each R20 is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(Ci-6 alkyl)2, Cnio alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, oxo, C3-12 carbocycle, and 3- to 12membered heterocycle; and each R30 is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(Ci-6 alkyl)2, Cnio alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, oxo, C3-12 carbocycle, and 3- to 12membered heterocycle; and R50 is selected from a substituent capable of reacting with a nucleophilic group on a Drug unit.
[00237] In some embodiments, for a linker of Formula (III), R50 is selected from a substituent capable of reacting with a nucleophilic group on a Drug. In some cases, the nucleophilic group on the Drug contains a nitrogen. In some cases, the nucleophilic group on the Drug contains an oxygen. OyT
[00238] In some embodiments, for a linker of Formula (III), R50 is selected from OH .In Oyo" some cases, R50 is selected from -OH. In some cases, R50 is selected from Cl . in some Oyj” cases, R50 is selected from °2N .
[00239] In some embodiments, a Drug-Linker of Formula (X) is selected from:
[00240] In some embodiments, a conjugate of Formula (A), is represented by: antigen-binding portion thereof, wherein the antibody or portion thereof optionally without the C-terminal lysine, K1 is as described elsewhere herein, and DAR is selected from about 1 to about 8. In some cases, PTK7 is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the DAR is about 8. In some cases, the DAR is as described elsewhere herein. In some cases, PTK7 is selected from an antibody from Table 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00241] In some embodiments, a conjugate of Formula (A), is represented by: antigen-binding portion thereof, wherein the antibody or portion thereof optionally without the C-terminal lysine, K1 is as described elsewhere herein, and DAR is selected from about 1 to about 8. In some cases, PTK7 is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the DAR is about 8. In some cases, the DAR is as described elsewhere herein. In some cases, PTK7 is selected from an antibody from Table 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00242] In some embodiments, a conjugate of Formula (A), is represented by: antigen-binding portion thereof, wherein the antibody or portion thereof optionally without the C-terminal lysine, K1 is as described elsewhere herein, and DAR is selected from about 1 to about 8. In some cases, PTK7 is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the DAR is about 8. In some cases, the DAR is as described elsewhere herein. In some cases, the PTK7 is selected from an antibody from Table 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00243] In some embodiments, a conjugate of Formula (A), is represented by: antigen-binding portion thereof, wherein the antibody or portion thereof optionally without the C-terminal lysine, K1 is as described elsewhere herein, and DAR is selected from about 1 to about 8. In some cases, PTK7 is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the DAR is about 8. In some cases, the DAR is as described elsewhere herein. In some cases, PTK7 is selected from an antibody from Table 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom. In some cases, Lisa PTK7 antibody. In some cases, the PTK7 antibody is selected from Table 8.
[00244] In some embodiments, a conjugate of Formula (A), is represented by: antigen-binding portion thereof, wherein the antibody or portion thereof optionally without the C-terminal lysine, K1 is as described elsewhere herein, and DAR is selected from about 1 to about 8. In some cases, PTK7 is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the DAR is about 8. In some cases, the DAR is as described elsewhere herein. In some cases, PTK7 is selected from an antibody from Table 8.
[00245] In some embodiments, a conjugate of Formula (A), is represented by: antigen-binding portion thereof, wherein the antibody or portion thereof optionally without the C-terminal lysine, K1 is as described elsewhere herein, and DAR is selected from about 1 to about 8. In some cases, PTK7 is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the DAR is about 8. In some cases, the DAR is as described elsewhere herein. In some cases, PTK7 is selected from an antibody from Table 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00246] In some embodiments, a conjugate of Formula (A), is represented by: Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the Targeting Unit is bound to the drug-linker via a sulfur atom. In some cases, L is a PTK7 antibody. In some cases, the PTK7 antibody is selected from Table 8.
[00247] In some embodiments, a conjugate of Formula (A), is represented by: wherein each Lisa Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, a conjugate of Formula (A), is represented by: wherein each L is a Targeting Unit; and each DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the Targeting Unit is bound to the drug-linker via a sulfur atom. In some cases, L is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6; PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
[00248] In some embodiments, the conjugate or salt of Formula (Aa) is represented by: in some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, the antibody is UC-961. In some cases, the Targeting Unit is bound to the drug-linker via a sulfur atom. In some cases, the antibody is an anti-PTK7 antibody. In some cases, the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6; PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
[00249] In some embodiments, the conjugate or salt of Formula (Ab) is represented by: , wherein L is the Targeting Unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, the antibody is UC-961. In some cases, L is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6; PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
[00250] In some embodiments, the conjugate or salt of Formula (A) or Formula (Aa) is represented by: wherein L is the Targeting Unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, the antibody is UC-961. In some cases, the antibody is PTK7. In some cases, L is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6; PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
[00251] In some embodiments, the conjugate or salt of Formula (A) or Formula (Ab) is represented by: , wherein L is the Targeting Unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, the antibody is UC-961. In some cases, the antibody is PTK7. In some cases, L is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6; PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
[00252] In some embodiments, the conjugate or salt of Formula (Ab) is represented by: wherein L is the Targeting Unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, the Targeting Unit (L) is an antibody. In some cases, the antibody is UC-961. In some cases, the antibody is PTK7. In some cases, L is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6; PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
[00253] In some embodiments, the conjugate or salt of Formula (XX) or Formula (A) is represented by: WO 2025 / 222052 (PTK7y--- OyC rYi F ° c (PTK7)-—---— xd J H O i H OyO yy.NH TTjSn F^^N ^ HO (PTK7)------- ) H 0 1 H % "Tii PCT / US2025 / 025244 168 O ~y ^NH °h % 0 V HN^yH I O^NH HO HO H 0 h 0 H O > SrN^N^TN^N^rN^N^fN^N^N^OH o HO HO HO H 0 w° cT 10*1^ ) \O -J DAR --- 'NH °> % 0 T° 1 oAih h o H o Ho ho H o 1 LYN^N^trN^N^fN^N^rrN^N^iTN^U'NH2 0 HO Ho H 0 H o o x0 DAR , 0 ^'NH °h 0 V I T O^Nx 1 0 1 0 1 0 1 0 1 9 / TN^n^n^n^n^n^n^n">tn^oh H O 1 0 1 0 1 0 1 0 "W ~y> H0T~< 7 DAR DAR DAR. 9 (PTK7U^ 0 H O I F V'Av o / k H 0 T (PTK7)“___ J h o . O H c F H Q H (PTK7)^ h S o CX % °> % k o V > O^N' I O 1 O 1 O 1 O 1 o OyO ^\.NH 0 1 O 1 O 1 0 1 O Try? n HOYJ J \ o DAR 0 0 ■% s ex % H 0 ''Y0 hnxu^^['nh l cAn" । o । o । o । o । o / < °Y° lsYN^'N^|fN^11'N^fN^'N^n'N^N^irN^'OH YY'NH o 1 o 1 o 1 o 1 o JCXM HOTY / DAR , o H 0 YN-yN^NH H 0 O' % O' % 'x 0 1 H 0 V / hn^—Ynh ' H 0 CYNH , 0 1 0 , 0 , 0 I 0 °Y° Srn^N^rn^'N^rn^'NYr'^NYr'^oH y\.,NH 0 H o HO H o HO GuSny0 ho-xY x° J DAR. , DAR DAR DAR DAR DAR , wherein (PTK7) is a PTK7 antibody or a PTK7 antigen-binding fragment thereof; and each DAR is a drug to antibody ratio. In some cases, the PTK7 antibody is selected from Table 8. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00254] In some embodiments, the conjugate or salt of Formula (XX) or Formula (A) is represented by: WO 2025 / 222052 (PTK7y--- OyC rYi F ° c (PTK7)-—---— xd J H O i H OyO yy.NH TTjSn F^^N ^ HO (PTK7)------- ) H 0 1 H % "Tii PCT / US2025 / 025244 193 O ~y ^NH °h % 0 V HN^yH I O^NH HO HO H 0 h 0 H O > SrN^N^TN^N^rN^N^fN^N^N^OH o HO HO HO H 0 w° cT 10*1^ ) \O -J DAR --- 'NH °> % 0 T° A^yNH I oAih h o H o Ho ho H o 1 LYN^N^trN^N^fN^N^rrN^N^iTN^U'NH2 0 HO Ho H 0 H o o x0 DAR , 0 ^'NH °h 0 V I T O^Nx 1 0 1 0 1 0 1 0 1 9 / A ^n^n^n^n^n^n^n^n^n^oh H O 1 0 1 0 1 0 1 0 "W ~y> H0T~< 7 DAR DAR DAR. 9 DAR DAR DAR DAR DAR DAR wherein (PTK7) is a PTK7 antibody or a PTK7 antigen-binding fragment thereof; and each DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00255] In some embodiments, the conjugate or salt of Formula (XX) or Formula (A) is represented by: DAR DAR DAR DAR wherein (PTK7) is a PTK7 antibody or antigen-binding fragment thereof; and each DAR is a drug to antibody ratio. In some cases, the PTK7 antibody is selected from Table 8. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00256] In some embodiments, the conjugate or salt of Formula (XX) or Formula (A) is represented by: , wherein (PTK7) is a PTK7 antibody or antigen-binding fragment thereof; and each DAR is a drug to antibody ratio. In some cases, the PTK7 antibody is selected from Table 8. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00257] In some embodiments, the conjugate or salt of Formula (XX) or Formula (A) is represented by: DAR DAR 5 DAR .or "° ^DAR wherein (PTK7) is a PTK7 antibody or antigen-binding fragment thereof; and each DAR is a drug to antibody ratio. In some cases, the PTK7 antibody is selected from Table 8. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP-HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom.
[00258] In some embodiments, the conjugate or salt of Formula (XX) or Formula (A) is represented by: N H N H 0 H OyO ,NH 0 ,NH 0 o H O I O I O I O I 0 ^N^N^AN--YN^N--yN^N--YN^N'-Y0H XI I O 1 O 1 O 1 O 1 0 kJ I kJ I kJ I kJ I 0 ^N^N^N^N^N^N^N^N^N^NH2 K 1 o 1 o 1 o 1 o 1 o <PTK7) DAR PTK7) DAR wherein (PTK7) is a PTK7 antibody or an antigen-binding fragment thereof; and each DAR is a drug to antibody ratio. In some cases, the PTK7 antibody is selected from Table 8. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is determined using RP- HPLC as in example 40. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the PTK7 antibody is bound to the drug-linker via a sulfur atom. Table A: Specific Conjugates of the Disclosure Conjugates Antibody (L) L— ° o ________An^^nh % h 9 i h 9 V I hn^~nh > 0 H 0 O^NH 0 ^,NH H O' 0H p J HOVo DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- ° 0 ______An^Anh Ck % , 0 , 0 , 0 , 0 , 0 > ^.tNH 0 1 0 1 0 1 0 0 uXh° F n vA i J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- 0 ? ----- '-'o S I 0 h ? I h ? Z Y o NH | 0 |_| 0 |° |° H 0 A 0^0 . V Y N Y N Y N Y N Y 0H ,.»NH 0 1 0 1 0 H 0 1 0 XX Xa —< 0 hoA [ DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— ° £ ^o S °> ^0 / XVzi 0 A ° oX I 0 H o I O I O H o 0^,0 k___,N.___\, / >^zNsAm / ^N.______■NsAm / ><zNxAmu rr n tt n tf n it n ti nh 1 II 1 II 1 II H II 1 II / XaNH 0 1 0 1 0 O 1 o XXzzl \ o hoY DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. -- 0 0 L_____________'X l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. s 0 0 / k O A I o । 0 । 0 ! 0 < °Y° 1 II 1 II H II 1 II H II ^NH O 1 0 O 1 O 0 P < H°z ° J DAR Conjugates Antibody (L) L------- o O X S 0. ko h p ! h ? \ ^Nz, A. x , Y X / \ ,'NH i <r O i TY k o X. o k.X. k X / NH O | ° 1 ° 1 ° / Y XyXyXyAy"’ 0 । 0 H 0 । 0 H 0 'TXX'-f F N Y\ / )--\ '“Y o v H0 / l J E )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. <00 L~ —XXh '"Sd s 0. 7 o H o Uy 0<^NH o H A V ^n\n^oh fWX 0 ; H°o^o \ P Z ' 9 1 H o hox 0 ^V / 0H HO7 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— --Z~N^^NH S L h2n H rA n O Z °AH 0 oYho . H hnX I °Y° 'AW™ A A'"® H A » O . f-\ Oy0 ( HTh0 ^YnAn\nY Ah°Y P F^N^y. ° = H °o\h ..... Y) o X; ohn^o A a Ymj HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) H 0 H O H 0 L- H o H o k X -< X >- H O । h 9 । / ° H 0 '-^'Y oA 1 0 O 1 0 1 0 1 o ov° AN^N^NXXYrN^NXrN'"'%''Y '“'“n ^.,NH 0 1 0 1 O 1 0 O fXJXnx° / ° HO’W V "° J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. N=N / ssk l y-y) 0 nY^Ajh 0 % 1 -y 1 H ? 1 H 9 ''X, 1 Y / n'Y'C'I hn^A 0 xk H 0 kAA 0XN^ ! o ! 0 1 0 1 0 1 0 o^o ^X,.,NH 0 1 0 1 0 1 0 0 XjUCnY aLx H° ° _A DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. 0 0 s ex % ex % ' hnX-^nh 0 X H 0 CX> Cr Nz 1 0 1 0 1 0 1 0 1 0 OyO \rN^NY''l^N^'^N'YN-AXl'^0H ^..NH 0 1 0 1 0 1 0 0 F nXX . yp ho-H J c JAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— 0 A s CL % : Wo / X , o » , X , 9 , 2 yy,NH 0 1 0 1 0 1 0 0 UXn-X F N Vh v \o HO’tA . \ 0 c JAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. H 0 H O H ° L Xn-'yXm'XAh Ho H 0 X -< x > H O i h 0 '"Y / o X^ H 0 XXyJ oXh । o । o । o । o । o NH O HO HO HO H O yW^ zo JI J J NA 0 H0*W A xO J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) H 0 i H 9 P 'Yn' / 'n\nV^n o °^o^°^nA—nA--- oAH o H °Y° H 1 0 1 0 1 0 1 0 1 0 n 0 1 0 1 0 1 0 1 0 I YUna ^Y~\ zo H0 \0 [ .—L )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. H 0 i H 9 0 Uh J H °Y° H O^N^ I 0 1 0 1 0 1 0 I 0 ^..NH VN^N^NAA^N'AA'''YN-AtN-yN.ANH2 n 0 1 0 1 0 1 0 1 0 IirH f n vA zo < HO^ [ ,-L )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. H 0 i h 9 P —L 7 A 1 H A ll A .NH n A T N T o' _ < o^o o nh uO h o hO h 9 h 9 < 'YJj3h° F^^ \l7~\ z0 HOVo DAR |_| 0 i h 9 P SXH S Us^n^NH H °v° H O^NH H 0 H0 H Q H 9 H ° ^.,NH ^n^n^n^n^n^n^yn'^Ln"'yn''^'nh2 jPXjSna0 F^r-f A I 0 H°Vo > D -L AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L--- ° 0 A S 0. % H 0 ! H 0 X. A... umAxx«NH > T r N Y T N HN A 0 cr nh 0 V °:sQo ^,.NH H 0 0H A \ / ° J HOVo DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. x- 0 0 L----- 0 S % y H ? ! H 9 X Ci 6 s Cm n Y O NH । 0 H 0 1° 1° h 0 Y Y '^ N Y '^ N Y OH 1 II 1 11 1 11 H 11 1 11 ,»NH 0 1 0 1 0 0 1 0 \AAc>^ zo XX X / y 1 F'^-^'N C-y v_ ' \ / ° A H0 / X DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. A ° o mAn"^A^nh L— A, CL % J H 0 1 H 0 X° XV-AA^n hn^^'nh 0 A H o XCyJ oAh ,o H o । o । o H o OyO XN^n^n^n^n^n^n^n^n^nh zx.NH 0 1 0 1 0 H 0 1 0 AXXnA - h°A° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. S' 0 li _____] L o , o ,o ,o i n N n N n N n N n 1 II l II H II I II H II 0 1 0 0 1 0 0 XXX / ~C I W~A K_ o \ "“p ^dar l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) L--- ° 0 °> X) 0 A H o kAy1 0Anh ! 0 ! 0 ! 0 ! o — ,NH 0 Io H 0 Io H 0 ° < H / o J z yDAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- ° o "'A l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; ^^0 S Ck % H 0 i H 9 A^ '^n' / n\Vn hn-^^-'Nh 1 0 A H 0 kAyJ o^NH 0 ■ H V. OyO kANAyN-Y^OH A O,NH H ‘h h ? I o rrrw Mvl 0 = H°o\ho \ ,° "- 1 9 1 H o HOtt A AV™ A_ °HO J DAR Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. ° o ____An^^nh L—" ’ S % H 0 i H 9 JY / nYY* N HN^'^ 1 A. o A. H 0 qA 0 . H A OyO CANA,NyX~OH / H CT >0 vQyw ^y^n\nQ F^AGC 0 = H °o^o V P Z ’ 9 1 H o l HOVo 0 AN Wnh HC> A DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. r 0 0 L S <x L H9 h r> n n A0 A AAVa hnA^-nh 0 hnA A 0 A H 0 Ak^ oAh 0 . H A A j °y° AVaoh Aooh r a,nh h V^h o . q GLo nA? ^nhV\G fAA^GV 0 = H °oAh oay GV AGo -A 0° jA oHAo HOvo 0 ANHrM v H o J U V. HO y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- r ° o ___________T'N'^A'NH | l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. W S 0. L h2n h r\ n O A0 o\N / n i—। 0 i i-i Qi * b AnANAn hnA^ 0 hnA I 0 A H o A- / 0Ah o H H K V °y° Av<0H A0 A'NH “A H o , r\ CAo YTAnA A^tirl 0 ■ °A> Aw \ p -'A 9 i A oHIAo A ho-A 0 aVn4) J M H o J A -7 HO DAR Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; O 1 O 1 O 1 O 1 o 1 0 1 O 1 O 1 O 1 O H 0 1 H Y __. ? h A-——— O^o H 0 o ---L 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; mTn? 10) L is PTK7-9; JI ^<<4. / \ f^^AAa y,o ll)LisPTK7- HO^ J DAR 9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. <- “A l)LisPTK7-l; 2) L is PTK7- A-y^J^nJi OH h 0 i h °YNH 0 0 H 0 H 0 H S A, AMA n --- n 1 m " T 1 9 H f\—• 0 H 0 0^0 H 00 —L 1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 1 A 6) L is PTK7-5; A p < H0Y0 y DAR 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. n^nh2 h 0 , ANH ° H 0 H 0 H 0 H J n Y I ri _ _____— ——L 0 H °YV—------ J 0 A H o I >. 0^0 H 0 o F N 1 HOVo J V x ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) H Q. qh r n u 'o _ O^NH 0 H 0 I H T WnVA 0 H Yv-—’L 1 0 A H O AA°^~nyAT 0^0 H o 0 > I p HOVo J ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. 9 h 9 h Q h Q h o H 0 . h°YNH 0 0 ° ‘° ‘° ^N,. AmA-N^X _ 0. ______ L Y । N n Y J 9 H _______ o A H o I OpO H 0 o p- O-'^H p HOVo J - -Aar l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. C 0 1 O I O H 0 1 0 Q NH 1 0 H 0 1 0 1 0 H 0 H ° I H Y i ' / AVA o H Yy——---- ) 0^0 H o o I A O'NH i xAa-? p HOVo JDAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. C' hoa >NH OHN HN—< ZX J" L w x yn H^o nho '' o^NH O=o °Vn1 oh 7- N J XZ^f 1 \ HN—( HN--Z q. H \ ( hNH o HN^o °^nh < °>-<Nq \ HN\ )-NH CJ / j A NH n 0^ / H 9 1 H 1 V’AV-A o h Vv—-——-L o J H 0 OyO H 0 0 ZX.'NH HOVo J V DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— ° o "A ____________An^^nh ex % H 0 I H 0 A° vN'AVn hn^'nh O H 0 (Anh 0 1 °Y° A- 1 ,nx H o 0H > O^NH । zNykz oA । y O^N^\ / N-\Y^ < "Hd > DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) L— 0 9 ~0 ____________An^^nh '^o S Ck o H 0 . H ? O V'AONY^ hn^^'nh 0 H 0 o^NH 0 0^0 01..^^0.^9 \ / Ok H 0 ~0H O. cAnh ( 0 1 1 ( / NA h \ H0 / < yDAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— 0 0 --. _______An^^nh A % H 0 ■ h 0 o o ay 7¼¾¾1¼1^ O^NH 0 1 1 J. 0 N"\ , xoO° ,- V_ N-\_ HH(5 " _ / DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; Conjugates Antibody (L) 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— C ______An^^nh S cl % H 9 1 H 0 V O^NH | \A^O I ° 1 O^N^, Yvo hh^ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) L— ____k^NH 0. % H Q 1 H 0 V Yn'A\n^i hn^'nh W S 0INH0 H OyO OlNA,NY~0H H o )=0 X Y^Xn^Q vY1 o = H o Y-nh If u I 0 ? 1 O X j NH^ in ho < Aj? > r~\ / N-\JX H > HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— 0 o _______Xn^^nh S 0^ % H 0 . H 0 V Y^n^YY hn^-'nh 0^0 |H ? I H XyY h o Xo X YU.W 1 X 1 0 = H 0 „AnH 1 zNyV 0 A 0 O ' o^nY - H o J < H0 < / nA__U 7 J Y. h nW Y HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14.
[00259] In alternative embodiments, the specific conjugates of Table A are also envisioned with no stereochemistry defined. Table A-R: Specific Conjugates of the Disclosure Conjugates Antibody (L) L— o O _______—%H % H 0 I H o V L V' / nAA^, hn^^'nh < o 0 o^NH 0 OyO H O' 0H v P J HOVo DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. l)LisPTK7-l; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L 0 0 'x ------An^^nh Ck hn^^-nh 1 0 H 0 O^NH H Q H Q H Q H 9 H Q ( XXXW I p HOTA ) x DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L- k ° o -- k % 0 / k H 0 k=k> o^n' I 0 1 0 1 0 1 0 1 0 O^O o 1 0 1 0 1 0 1 0 YXXW F N^k> k~\ k HOVo - c •AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- o 0 A % i_i 0 | H 9 hn^-'nh ' 0 H 0 I 0 1 0 1 0 1 0 | 0 / Ov6 ^..NH 0 1 0 1 0 1 0 1 0 IZXW V>-\ < \_P HO'W J c )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- 0 2 A % I । । 0 | H o hn^'nh [ 0 H ° O^NH 1 0 1 0 1 0 1 0 | o v 0H Xzxw v. _y HO<1 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; Conjugates Antibody (L) 15)LisPTK7-13; or 16)LisPTK7-14. L- 0 0 --- 0. % H 0 1 H Q I 0 H 0 cr nh 1 0 1 0 1 0 1 0 | o X stay nh- OXK Y J H0T\ x° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) 0 II L—--A S 1 0 H ? | H ? Jof i w.......r A '^0 CT NH । 0 h 0 |° |° H 0 \ 0^0 kA 1 , / , A A,^\XA,^A / L / \ / Nx 1 ,, :O JO N |C N fC N ^rC N fO OH / 1 11 1 11 1 11 H 11 1 11 / - ,NH 0 1 0 1 0 0 1 0 JifiX / A F"^N't?- / K o hoAJ I DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- 0 A ^0 S 0. % vn, H ° ° AA^-A O^NH 1 O 0 । O 1 0 u ° - 1 I II H || 1 II I II H || 0^.0 A / N-A^k,^___N^k, / \.N.A zk,N.___Az\ / N. A, n N Y N 7T N 7T N 7T NH 1 II 1 11 1 11 H 11 1 11 / -. ,kNH 0 1 0 1 0 O 1 O F'^N VZ"\ ho*Ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L----- O O ______________________"■'X S 1 ° A 0 MA OANH ! o ! o ! o ! 0 I V UnnX,,^n nMn^oh A 1 II 1 II H II 1 II H II ^NH 0 1 0 0 1 0 0 'XaScn“C \ o < H°n DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L------- ° o "Y __ H S o. o H ? I H ? A Y'AV-n HN^—yNH I NH | 0 | 0 | 0 | 0 / Y VAyAyAyAY"’ / \aNH O । O H O । O H O xAz / y''. zO XX X / M N A\ z)—x O X Ho / 0 J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— f o 0 'xj S % i—i 0 i H Q V'A'Vyy hn^YNH 0 xk H 0 O^NH 0 . H O^b ^-•NH H 0 >=0 0 = h °oyo A P z I 9 I H o HOVo H0? DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L— y ° o -- —_ 0. % HN-y-™ 0 xk H 0 kA^X1 Cr NH 0 . H 0,-.0 O<N7yN^X-0H X^'NH H 0-^0 yQyN y F^AyC 0 = H °Oyo V P Z ' 9 1 H 0 HOVo MyA y ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L— r i u h9 h n n O A0 u 0 | H Q [ * 0 ‘T'-x V' / nVa hnAnh 0 HN-J3 0 A H 0 0Ah o . H HN~ ' y °Y° AVA A>o < n" h °n « fl I O Ayo ITTn? A'A Yl o y0 cAa hA- A o -z t o . Ly oHN^o A Ay A Ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L— A L h2n h r\ n O A O^^'Y^N H 0 i H 0 T * 0 A o a H 0 UJ 0Ah 0 H hnA I °y° —Vy^™ a>=ooh z rYH H Vn h o . r\ CCo | mtn? rl ^nhM p 0 = H 0 0¼ 1F V V) -¾ 0 A? oHAo MOVo HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) H ° H O H O L n^N^YN^N^YN^NH H o H 0 kj X J X o > 1 H 0 I H 9 / 1'NH 0 X. H 0 XU o^N'' 1 0 1 0 1 O 1 O 1 O 0^6 XnX<n^n^n^n^An.-yn.^n^yn.^Aoh r Xh o 0 O 1 0 1 0 nW V / ° H0*W V 0 J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— N=N yy o 0 A % CL % H 0 i H 9 ''C hn^^i'nh 0 xC H 0 Cr Nx 1 0 1 0 1 0 1 0 1 0 0^6 ^..NH 0 1 0 1 0 1 0 0 YjXw F^^ v)~\ H0 k o A )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. 0 0 s 0. 0. H 0 ■ h 9 S^° / HN^^r'NH 0 H ° Cj A । O | 0 | 0 | 0 | 0 oro ^Y'NH 0 1 0 1 0 1 0 0 Yxtw0 vjH \ / ° A. ho*W / \O E JAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L—.0 0 s % Jo o V A^,nh I ] 0 H 0 Q 'l' । 0 | 0 | 0 | 0 I ? f o^d ^.,NH 0 1 0 1 0 1 0 0 'TXXW F N th < a. p ho-Ho > DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. H 0 H O H 0 L n^n^n^An^n^Anh Hq H 0 X 0. A .. n . .. o X° / hn'^'T' o .A, H o oXh । o o । o । o । o ovd ,NH O H 0 H 0 H 0 HO TXi?ho VzH '~k 0 I. HO<k V u DAR - / H 0 i H 9 p SAh S Vk^NH h °y° i 0 i 0 i 0 i 0 i 0 ^..NH V^N^^N^n'^N^'^N'V^OH Vvk 0 0 1 0 1 0 1 0 1 0 I Y X N~c L H°Vo .—-L DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. H 0 i h Q 0 y AH o nh h Q^r > °Y° H 0*y I 0 I 0 I 0 1 0 1 0 O'™ vWx 0 0 1 0 ' 0 1 0 1 0 T T Tj n-c I o p < ho-H J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; Conjugates Antibody (L) 15)LisPTK7-13; or 16)LisPTK7-14. __-L H 0 ■ H „ „ 9 0 ’ 'YN'rANATNY^N o —.—• H yA" 1 ) °v° H O^NH H 0 H 0 H 9 h9 H ° < ^.^NH CN^N^rN^tN^rN^N^fN^lN^fN^0H o o H° H° H° 0 p ho-H J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) J H 0 1 H _ n ? P S U^n^nh h o<^ °v° H CT NH H0 HO h9 h9 H 0 <VNH lyTW ° < HoW J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L--- ° 0 ___________An'^xAnh s Ck % h o । H o S*0 y T [ n n hi hn] ( 0 Ax o kAA o^NH 0 oYd yx,NH H 0 0H y ,o J HOVo DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- ___ tWWX J ,, 1 9 .9 .9 L ^,NH 0 H 0 H0 H 0 H 0 )&W Y. P < HOVO J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L -< / - q 0 ___An^^nh S % H 9 ! H 9 'Yn’ / 'n\'ny^n HN^^i-^n 0 H ° O^NH 1 0 1 0 1 0 1 0 1 0 Ov6 ,^IH 0 H 0 Ho Ho Ho AAw / \ p / HOVo [ )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. / - 0 0 _ 0 S ^0 / H 9 ! H II V jww r 0 NH | 0 |_| 0 |° |° H 0 0.,-. ,6 ^ / N. / ^klz^ / N,Akl / \,N. ,, N r< N N rf N OH 1 II 1 H 1 II H II 1 II / / .*NH 0 1 0 1 0 0 1 0 X A XNA l N / / —\ V_ v ( o ho*Ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. A ° o L— S °> % w-AVrN Hn^vh ( 0 H 0 o^NH | 0 H 0 I 0 | 0 H 0 OyO / x^NH 0 1 0 1 0 H 0 1 0 'XXX^ J L ^-Q DAR HOpo l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; Conjugates Antibody (L) 15)LisPTK7-13; or 16)LisPTK7-14. / - 0 0 ] L""'^ ° WYwbf,. , o , o , o 0^0 L^N.______"A-m'XzN___^.OH n N TT N If N TT N if 1 II 1 H H II 1 II H II ^.ANH 0 '0 0 '0 0 'XXX / -C V. 0 J ho / 4 -^dar l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L--- ° 0 °> 0 A H ° 0XNH i 0 ! 0 ! 0 ! o Z" 0 । 0 H O । 0 H 0 AoOA 'k P < Ho / O J 7 y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- 0 2 -------A N N H ^^0 S Ck % u 0 i h 9 t / Ayn O X H 0 UM o^NH 0 । h X 0-X UXN.A0H P FT H A H ? I O rirN? uvN / ANY fAAI 0 = H °o\h0 L / ° "'X ? 1 H 0 Hotl 0 An,Ah V °HO J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. ° o ____An^Anh L—"" ” S Ck % H 0 i H 9 <SAh S oanho h y oy C>-NyN^~oH / ^x.NH H >0 0 = H Oq^nh V ,° " ' 9 1 H o I HOVo 0 fly / n ho^ y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L— A 0 2 v. 0. L H9 H O n O M° oAApN Y^'HN A^ 'NH ° 0 HN-M ° AH o VU 0A^h o h HN\ k °Y° CAna^n^-oh J>ooh / n~NH H °n h ? i o cLo o = h o O1NH X Y V V Yf° ? |Y oHMo HO\o o vAo V. HO^ J) D AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- ° 0 _________An'^I'nh 0 °> L h2n h r\ n O 1*° YAVtCn hn^V'Nh 0 0 hn-J3 °XH 0 ‘ AH? 1 H Hn\ °Y° JAooh M'nh Hon°H ? 1 o CG nrH° vf^nNi AhVyY fVnY X 0 - H 0 V Yr- V Mo Mf° 0° yj OHN^o V hoMo YWnA \ l-j H o ) Lj - HO D / \R l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 15)LisPTK7-13; or 16)LisPTK7-14. C 0 1 0 1 0 1 0 1 0 _ 1 0 1 0 1 0 1 0 1 0 H 9 i H i ,-, 0 H Ya________- ---L l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. ) OyO H 00 XXXNX V>-\ HO^ DAR Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. O 1 O 1 O 1 0 1 0 ^N"YN'^'N">fN'^N"YN'^l'N"VN'^N"YNH2 „ 1 O 1 O 1 0 1 O 1 0 H 9 1 H 1 „ __ V-AVyS o h °rv---——— n X H r> Il y A c> n kl / ---L 7 “ N -Q \ A ,6 H O 0 < ro ( VyT V-A V \ U J —. . —k DAR u o . U °VNH 0 H° HO H 0 H S H v I H 1 _ __ yAW o H —-—' o A H o Uk^^O^-^N^^NY' OyO H 0 0 / yNH ^ucXn^ ^,0 < HOv y —L DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. NH2 h 0 , ANH 0 0 H° HO H 0 , n ---- T T N T Tn 0 u i\__■—— J o A H 0 I A OyO H 0 0 A XXX>~? p 1 ho^ \ v x DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. H Q, Q|_| r T u 'o _ O^NH 0 H 9 J H T Y' / nY-A 0 H 1 o A H o -= / 0^0 H 0 o V I ^.xNH XXXk / 9 F'^'N p HOVo < ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. C" 0 | 0 । 0 H 0 | 0 n NH 1 0 HO 1 0 1 0 H 0 h Q i h Y „ . VN' / n\NA 0 H ------ J 0^0 H 0 0 Y ] O'NH 1 V>~\ \,o HO'H ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7- 14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; ° 1 ° 1 ° H ° 1 ° 8) L is PTK7-7; h 9 h Y n _n, „ o ____ IT T N V Y i 9 h TV_— ------ --L 9) L is PTK7-8; o A H o « rv 0 H o o 10) L is PTK7-9; O'NH \>- ll)LisPTK7- xxxa 9EL; A> DAR 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. l)LisPTK7-l; O । O H O | O H 0 A^N^N^N-Aj^'YN-Aj^'YN-A)H NH 1 O 1 O 1 O 1 O 2) L is PTK7- H 9 I H ] n V'AVA 9 H Vv_---- .-----L 1EL; 3) L is PTK7-2; 4)LisPTK7-3; 'AaSoA 5) L is PTK7-4; F^N lA \,° ho'tA 6) L is PTK7-5; v \0 _y DAR 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. O । 0 h 0 | O h O NH 1 O 1 0 1 0 1 0 H 0 | H 7 ___—L YAv / o H Vy--—— 1 0 A H o 1 < OyO H 0 0 v / y.NH XxXN-f A. p 1 H0Vo J yDAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; Conjugates Antibody (L) 15)LisPTK7-13; or 16)LisPTK7-14. HO ''x CL nJLX°h ,. / X Th 5 0 = H O °yNH h oyvoH °T ° ZZN l'N >-OH -S'"' NH O 1 H J rx Z / < H 0 1 H 7 „ Z A v / nCU o H ( 0^0 H 00 O'NH xxiq- / X, p I HoZy J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) HO [ O. n^Am.\<nh2 1 x ? X i H S ft 0 i H 0 °yNH aWkA H Q >0 ^^Y^N-A-OH NH 0 1 H J n 0^ / k AV'AV'A 0 H ( o A H o Uk^N^O^o^N^^NY~--------------- 0^0 H o o L ^^.'NH XoQ-f Y ZO HO'TA J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L— ° o ____________An^^nh % h o । h o 'v0 hn^-'nh o 1 H o X u O^NH O O^O kA M \ IT N .S.-u H OOH A O^NH 1 zNy-V 0*0 1 J. C) N^\ >Y .- „ / N'vXj V v ' >DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L— 0 ? "A Sd H 0 . H 0 V'AVyA hn^'nh ° H 0 O^NH 0 JA h 0 oh V cAnh ( \Ay° ° 1 1 (An^\ <w I ho J v y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— C % H Q 1 H Q V o o Ct NH 01 1 J. 0 N^\ V_ N-\ / 7 Hh(5 " -J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L— o 0 ______An^^nh o. H o i h o 'v0 O_O ? J H h o Xo A.o 0 = H o / -W u ' XA VXh2 O^N^\ VJ H 0 ) xHp0 H0 I °Vn<o ) HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. Table A-S: Specific Conjugates of the Disclosure Conjugates Antibody (L) L— 0 0 _______—%H 0. % H 0 I H 0 V I hn^^'nh > o 0 O^NH 0 °Y° ^.NH H O' 0H A p J H0Y> DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; Conjugates Antibody (L) 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7-13; or 16)LisPTK7-14. L- r o 0 ---- S cl % 0 H 0 CT NH H O H 9 H 9 hO h 9 ( NH 0 H 0 Ho Ho H0 lYtw0 I y,o HO'jw ) x° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7-13; or 16)LisPTK7-14. L- 0 A ______—%H % I V'A'V'n hn^X I 0 xk H 0 o^NH 1 0 1 0 1 0 1 0 1 0 < -J \ ,0 _ . „ ho,Ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L- 0 0 ---An^^nh S CL hnA^h > 0 H 0 UxJ Cr NH 1 0 1 0 1 0 1 0 | o OXK V_ \ 0 J KOTA x° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) ° H L-f-- '-% S % h ? I h ? s* A O NH । 0 h 0 |° |° H j V / _,*NH 0 । 0 । 0 H 0 0 XX X / X N A\ \ '—( b ho*Ho [ DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- 0 A A S °Y % vn, ° ° O^NH 1 O ° i O 1 0 u ° * 1 1 II H || 1 II I II H || 0^.0 ___NxAKi / s,NxAhizK,N.___ n N Tf N 7T N 7T N 7f NH 1 II 1 11 1 11 H 11 1 11 z\aNH 0 1 0 1 0 O 1 O xx^nxi 't / ° ho*Ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7-13; or 16)LisPTK7-14. L----- 0 0 0. % ° ° O^NH । 0 । 0 । 0 । 0 X. V < 1 11 1 11 H 11 1 11 H 11 ^...NH 0 1 0 0 1 0 O XXX / X 'l / ° < H / ° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L------- ° o "Y __ o. o H ? I H ? A Y'AV-n hn^Y* I Y NH । 0 । 0 । 0 । 0 / Y VAyAyAyAy"’ / \aNH O । O H O । O H O XX X / M N A\ z)—x o X Ho / 0 J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7-13; or 16)LisPTK7-14. L— r _ u h9 h n A o i—i 0 i i-i Q [ * o 0 HN-A oAh 0 U / 0A , H hn\h y °y° yv<oH “>0°h < pfH H V” h 9 I r\ Cn^o rYrW5 yinl vj~\ 0 n°^N) hhn " y o -z t 0 . Ly oHN^o HOb &VjNHA5 y h° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L— 0 0 L h2n h r\ o o V° Y / nVy^i hn^y'nh ° 0 hnA o AH 0 0Ah o H hnA I °Y° A-N>yN^-0H _>°0H < PA H ° / ~n h 0 ■ f-x OLo [ TnV II F^N \5~x o\\ H V Y p t o .A oHN>o -¾ oYy-o HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) H ° H O H O L n^n^YN^N^YN^NH H o H 0 kj X J X o > 1 H 0 I H 9 / V'Au^uX t'nh 0 X, H 0 XU O^N'' 1 0 1 0 1 O 1 O 1 O 0^0 Xn^n^n^n^n'An''UnX'N^'yn-'-aoh O 0 O 1 0 1 0 XIx?nX F'^"U XL V / ° H0*W V 0 J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— N=N yy o 0 A % CL % । । 0 I H hn^vh 0 A H o kAA C> Nz 1 0 1 0 1 0 1 0 1 0 OyO yx-NH 0 1 0 1 0 1 0 0 Iaa0 NAk H0 k o A )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. 0 0 s 0. A 0. HN'U^^1-'NH f 0 A H 0 Uy oAt I O 1 O 1 o I 0 1 0 OyO yy.NH 0 1 0 1 0 1 0 0 YtxA0 F n ik \ / ° ho*t^ ; \o E JAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. 0 a A ^"^^0 S CL % hn^^^i’nh L o / k H 0 I 0 1 0 1 0 1 0 I 9 / ^,.NH 0 1 0 1 0 1 0 0 mV F N vh HO^ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. H 0 H O H 0 L n^n^n^An^n^Anh Hq H 0 X J X. > | u O I h 9 / V’AYXl o X~. H o LXX cXnh । o o । o । o । o OV° An^n^n^n^n^n^n.^n^ ,NH O H o H 0 H 0 HO TYXCm0 A__ / ° ( mm V ° J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; —-L 9) L is PTK7-8; H 0 i h YAY'! 0 / C H 0 yS ft OyO H \>NH "YA. / P ft p ^-.. ,NH H r „ o O N । 0 । 0 । 0 । 0 । 0 YYyYyYyAYYh 0 1 0 1 0 1 0 1 0 10) L is PTK7-9; ll)LisPTK7-9EL; 'NYY Yp HOVo 12) L is PTK7-10; 13)LisPTK7- DAR ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7- 14. s' l)LisPTK7-l; 2) L is PTK7-1EL; ,-L 3) L is PTK7-2; ft '^V'tY ft p ^.. ,NH H i-J 1 „ 0 4)LisPTK7-3; 5) L is PTK7-4; yS OyO H x^NH "Vy ,P 0 N । 0 । 0 । 0 1 0 I 0 \'NYN^NYN^NYN^NYN^NYNh 0 1 0 1 0 1 0 1 0 I2 6) L is PTK7-5; 'N^Co 7) L is PTK7-6; H°Vo L )AR 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. ____.-L H 0 ■ H n _ 9 0 H i ] M H O^NH H 0 H 0 H 9 H9 H 9 < o o H° H° H° 0 T TX'N-t ho^ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. J h 9 i h n _ 9 P A'AVn 9 < u AH o UyAy h A 0^9 H Cr NH Ho H 0 h9 H 9 H 9 ^..NH C^N^''^N^Nj^N^Nji.N^NjlNH_ Al n 0 HO H 0 H 0 H 0 TXXm ho-H J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L— -< _____An^^nh ) % h o । h 9 V- aWn hn^-'nh L 0 H 0 O^NH 1 0 1 0 I 0 1 0 | o ( YXIW> NY^, 1 H^° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. / - 0 0 _ / ^n'^^a'nh 'l 0 S y H 9 ! H || S*' Wi'wt * j O NH | 0 H 0 1 0 1 0 H 0 AA N r< N T< N rf N OH 1 II 1 H 1 II H II 1 II / \aNH 0 1 0 1 0 0 1 0 X A JlM V - J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. / - 0 0 L--- S °> J V'-AAr^N hn^^-'nh I / 0 A H ° oAh | o | o । o | o / ^\.NH 0 । 0 H O । 0 H 0 'k P < h°M ) 7 y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) 16)LisPTK7-14. L— ° o 'A Ck % H 0 1 H 9 ° hn^nh 1 0 H 0 O^NH 0 . H A. OyO A O'NH H °n H ? 1 o ITTny0 0 = h°o\ho HOVo 0 An,Ah V_ HO J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) C 0 0 V L—" ”” S 0. % H 0 i H 9 A° VVN'AN t NVn hn^-nh I A 0 AH 0 A*V oAh 0 . H A 0Y° ^nA'NV°H f H °H H 0 . YyVw j'7Avn? F^nAAA 0 = H Y P z T 9 1 H 0 HoA / SAAtN-Amu I \° OH AN ho y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. A 0 2 ___An^^NH A L Aq S °> A H9 H o n O y oA-VA z LaAvhVv 0 ° hnv A AH o Av V o . H HNV V ) °Y° W<0H / >ooh ( V'NH H AA° ? I y ^y° YlV 0 VAAnV1 ^nh°Vn-A F^nA V 0 = H o Vnh xV A AA -A0 o° v oHN^o HO\o A nNTN6 A HO^ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L- 0 0 ___________________________________________________________________I l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or ^^0 S 0. L h2n h r\ Ln oV / n °°HnJ 1 ° H ° oAnh 0 . H HN-S > °y° ’>ooh O'NH A” ? ! o ^r° TYVny0 V1n^h Jn1 ^nhMm-a Y 0 ' ' 9 I LJ oHhCo V HO-H 0 J H w ° y DAR Conjugates Antibody (L) 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. O 1 O 1 O 1 0 1 0 |ANArN^U'NArN^NArN^U'NArN^NArNH2 _ 1 O 1 O 1 0 1 O 1 0 H O 1 H T _____L V / nW 2 H —— >. 0^0 H O o A XXXN^L F^AAA 1 HO^ 1 - ' DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; Conjugates Antibody (L) 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. 0 _L 2 H J o A H o I A OyO H 0 0 O'NH ^CXXn-? F N 1 ho-H 1 x ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) J ^nh2 h o , ANH ° 0 H ° H 0 H J YAYA o h ——— J 0 A H 0 t "A 0^0 H 0 o Z” O'NH aa / A F N HA 1 ho-H 1 v x ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) H Q, Q|_| r T u 'o _ O^NH 0 H 9 J H T V'AVA o H 1 oXH o 0^0 H 0 o V I ^.»NH XXlCN^0 p HOVo J ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. h 9 i h Y _ , V' / nY^ o h Y ----- 0^0 H 0 0 V O'NH XXXn~? HOVo J - ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. 0 । 0 h 0 | 0 H 0 NH 1 0 1 0 1 0 1 0 H 0 I H n i \.N,. A.-M-A „ 0. ___---- n 4|] 9 h \___■ J o x< H o I A 0^0 H 0 o O'^H XXx>-? p 1 ho'H J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; Conjugates Antibody (L) 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. 0 । 0 H 0 | 0 H 0 NH 1 0 1 0 1 0 1 0 H ? 1 H 1 n ___—L 0 H V\__—------- OyO H 0 O V ^..NH XXx>-f p I H°Vo J v DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7-13; or 16)LisPTK7-14. r h0°\Ph ^NH OHN HN—( / X f .....NHO ' O,NH Ao <A°?H 0 vyA hL / W) HN^° J PAoh „°A V °>-NH . >"-<N4 \ hnA / -nh / 1 A °A NH n O^ / h 9 i h T _ V'AVyS 0 H °VA----— —l OyO H 0 0 O'NH XXXN~? p I HOVo J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or Conjugates Antibody (L) C <0H ^OH <°H AC0" HOXXho\ H° AcHN HO""^ Hu AcHN HN-^° H 0 1 H ° X 7 MtAANsA „ 0. > < n [NT n 9 h T\^ ( Y 0 A H o Uy-NAo^o^N^NY 0^0 H 00 X\-'NH XXXX L H°A DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— 0 9 ex % h o । h 9 'v0 V'Ahn^'nh 0 H o cAnh o 1 °Y° ^n^°:sP0H k 1 VN^ H d 0H > O^NH yX^Q । zNykz 0*S 1 4. 0^N"\ 'oH<? f / N-\ / j A H"d " J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— 0 u X S Ck H Q I H 0 V° vXXx hn^-nh 0 H 0 o^NH 0 ovo Q P I Xi H cX V cAnh [ oA 1 J. I H0 / y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) C l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L % H Q 1 H Q V Ct NH 01 1 J. 0 N^\ V_ N-\ / 7 Hh(5 " -J DAR Conjugates Antibody (L) L— _ °\ h j । h s O^NH [ rV° o 0 < A xh4—A o^U / / N-V / 7 Hh4^ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. Conjugates Antibody (L) L— C i j. A S Ck % h Q i h Q V kAV'X hn^^-nh u« s IV oiNHO h 1 °Y° CXN V,Ny'~0H Anh । 0 z H 0 nA-NH 1 C o X w. onV ho A / N-\J7 H AA > "° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14. L— o 0 _______An^^nh A s ex H 0 1 H 0 A rxYo / x o X NH 0 i h ' 1 । 1—kXNy"°H V N N J \ H o >0 ( 1 on u 0 i rA W> xx UA 0 = 0 0¼ 0 ? X ' O^V / nh. cTn^ H o ) JJ ho W / r-X < / na / v J V_ h rW - / HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16)LisPTK7-14.
[00260] Conjugates of Table A, Table A-S, and Table A-R, each independently have a DAR of about 1 to about 8. Conjugates of Table A, Table A-S, and Table A-R, each independently have a DAR of about 2 to about 8. Conjugates of Table A, Table A-S, and Table A-R, each independently have a DAR of about 2. independently have a DAR of about 3. independently have a DAR of about 4. independently have a DAR of about 5. independently have a DAR of about 6. independently have a DAR of about 7. independently have a DAR of about 8. Conjugates of Table A, Table A-S, and Table A-R, each Conjugates of Table A, Table A-S, and Table A-R, each Conjugates of Table A, Table A-S, and Table A-R, each Conjugates of Table A, Table A-S, and Table A-R, each Conjugates of Table A, Table A-S, and Table A-R, each Conjugates of Table A, Table A-S, and Table A-R, each Table B: Specific Conjugates of the Disclosure Conjugates Antibody (L) L— _____A_____Q ZE o. P 0^0 ZI o o o=? yCP O ° T / --\ X / LL. O / HO o=^”b o ZE l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l— 0 0 " ' '"A? A 0. ¼X9i'X -% I 0H v '"V - i Jh 0 H0A0H 1 1 (V3 / ° AcHN\x -WK <■ \ z° AcHNX H0'z% hoAAoh \ 0 Uri AcHN Xn y \ > DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; Conjugates Antibody (L) 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- 0 0 ---An^^nh (X % o o V HOJY°y°Y> HN^^r'NH I HO'" Y 'OH CAyJ o^NH HO H 0 h 9 h 9 h 9 A OH OVO Cn->'N-><n'^n^yN^-n-yn^n^yn^A0H ^..NH 0 Ho Ho Ho Ho XXXW i aL p H0*W J X° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) L- 0 0 "X ----An^Anh % 0 0 S*0 ho\°Y°^i HN^yn < HO'' T ''0H^T O^NH H 9 H Q H 9 H 0 H 2 f ^..NH 0 H 0 H0 H 0 H 0 \,0 ho<A y x° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- 0 0 'x ------An^^nh S ex % J 0 0 S*0 -. HO^Y°Y°><y S HO'' Y 'OH^T O^N^ 1 0 1 0 I o I 0 J, X 1 0 1 0 1 0 1 0 1 0 XXXW H0^q J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- ______^n^^nh Ck % 0 0 V ho1'y'^h^y1 oAr I o । o । o । o । o / OH 0^0 YN^N^rN^N^rN^N^rN^N^rN^NH2 NH 0 1 0 1 0 1 0 0 1XXW F n th < Y o HOTA _Z. c )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- --- % o o V Ho^r°YoYY hn^1—Y'nh ho'x-^ 0 NmN^aN^aN^aN^aOh o H6 h0 h0 h0 < XXXn^0 < F N -K c )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; Conjugates Antibody (L) 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- 0 0 l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. CL % 0 0 V I HaW^ hn n 1NH < H0' oh '0H 1 Jh 0 H 0 Ho Ho H 0 YjVnJ3 V \P J hoTA x° DAR Conjugates Antibody (L) 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L----- 0 O _______________ / -N ''■'"'W 0 oh ° Yh 1 ? | 9 | 9 | o it N if N Ti N it N fl 1 II I II H 11 1 11 H 11 / k?NH 0 1 0 o 1 o o \ 0 < HZ 0 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L------ ° 2 ~a NNH S 0. Un 0 V JL o Il । ™Y X y'NH V HO' 'OH O^NH । 0 । 0 । 0 | 0 ( 0H Y / \.'NH O । O H O । O H O 'TX^M° F N A\ / }—\ O v h° / 4 J [ DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. A" ° o L ------- s % 0 o S*0 HoWy. HN^-'NH / HO'Y'OH Uy O^NH 0 . H V y 0H o^o y | H o ..)=0 0 = °°Vo \ P z i 9 r h o HOVo o uV / 0H HO7 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) L— < ° 0 -------An^^nh A S ex % 0 0 M hoYtom^ hn^-nh oMh 0 , H 0^0 OtNl N^-OH ^.,NH H 0 >=O 'YyV'nM 0 = °<0 Y P 9 1 H o Y o bV / nh2 HC) DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— ° o ______An^^nh A S ex L H9 H n ° o v° °AnxVz HN'“^^]'NH ° hM° HO'V'OH cAhO . H hM ' 0H v mVm m i ryH H . o cCo nYw a ^hYi Yvaa maj, ° Mo oM hhn..... \ o "' t 0 . Ly oHNv=o »b oMHA> M ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— ° 0 --AbT---%H TO 1 0. L h2n h r\ o o s-° °V?' X- nAVVA hn^^X'nh 0 hn-J3 HO'V'OH Mk (Ah 0 . H HN'k I 0H O^O X / ^X^N.^OH X>0 > ryH Hon ” ? 1 1 nTH9 AN^h Al AHVxk fW{L 0 - H o O1NH A Hk A° 0 X? 0HN^0 Hob o-Aid H0Z DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. H ° H 0 H 0 L Ho H o X X \ > j o 0 V ( hn^j'nh HO" Y’OH XXX oXz I O O 1 0 O 0 OH Ovo 0 O 1 0 1 O 1 O kxxw F'^N vK ""k / ° H0*W V 0 J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; Conjugates Antibody (L) 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. N=N l yv o 0 % / \ ° 0 < hoV / x^ hn^'nh hctY'oh MU oAu I 0 1 0 1 0 1 0 1 0 0H 0^0 ^^,NH 0 1 0 1 0 1 0 1 0 XuCnY F n ch Y p HO'W V- x 0 __M DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) ___ o 0 S A % % \ 0 0 V , hoYoh Xj 0 NH 0 1 0 1 0 1 0 0 nYW n ik > a_p HO*tv / \ 0 c JAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. ° 9 s % 0 0^° HoV / y, HN^'NH ho-V"oh KAy 0*V 1 0 1 0 1 0 1 0 1 0 0H cA ^n^n^n^n^Yn^'n^Yn'^'n"'Yn''^oh 0 1 0 1 0 1 0 1 0 OzW F N VJH V aL / ° H0*W \ o c JAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; Conjugates Antibody (L) 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. H ° t! k nA L n^n-yn^n^¥n^nh Ho H o X o. ) o _ o V / H° ITri HO' I '0H CXZ O^NH I 0 I 0 I O I 0 I 0 0H ov° 0 H 0 Ho Ho Ho XlXXW f'^n VZa / ° H0*W u DAR hoVV°^n 0 ho'Y'oh MX^N^VNH h ZZ 0H n 0 H X 0 °Y° Ci N 1 0 1 0 1 0 I 0 1 0 o 0 1 0 1 0 1 0 1 0 T T Tj n-z p H\0 --- L DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. 9 n o 9 P o^n । o । o । o । o । o O'NH YN^N^N''^N"'''tfN'^'N^YN'^N^YN'^NH2 xAA_ n 0 1 0 1 0 1 0 1 0 aXXX \,o < ho^ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 0 0 o hAVVn o HO'Sr'OH kAy-NA^yNH H 0H cyo H ctnh Ho h 9 h 9 h 9 h Q yy.NH LYN^'N^'N^N^'N^N^IfN^N^ / N^OH WVn^0 0 H 0 H 0 H 0 H 0 F^^ \)~A y p H° \0 D —L AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Q o o HO^y \yN o Vo^^n^nV'''^ H0"V'’OH Mx^N^yNH H 0H 0^0 H o^NH uO H o H 0 H 9 h 9 ^n^n^n^n^n^n"'yn'^'n"'yn'-^nh2 KXj3h° 0 I y p HO-ft > D -L AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L---- ° 0 ____________ANZ'''A1H S 0. % 9 n M3 I A o 9 T \ HO^fV \^m um-V^'NH > 1 1 11 N HN v > / H0'- T "OH ~AMU ~ Ah 1 0 NH 0 0H Ck 0 < A / k 0 9 nL ^OH V o ) HCVo DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- f 0 0 ___] % 0 0 V ho Vr0^ hn^- 1 HO1' T ''0H 0 NH 1 0 1 O I 0 1 9 1 9 ^..NH 0 H 0 Ho H0 H0 < H°Vo J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; Conjugates Antibody (L) 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. o o ___] l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L % 0 0 V HoVr°V^ > " “H x 0 7¾¾¾1¾^ mv x° DAR Conjugates Antibody (L) o 0 L—' 0 \ 0 0 0 V 7 ho-\°Y°\^n hn1—t'nh V \ vl 1 L K j 1 / HO' Y 'OH O^NH 1 0 u 0 I 0 i 0 u 0 >—■ । । 1 i'll H 11 'll 'll r"1 11 0H Y ^\jNH 0 1 0 1 0 H 0 1 0 \ F^^NYY V. K o _y Hoy o DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. C o o L—- S % 1 o 0 Co Y “Vf VN HNC‘NH HO' Am °h tn* I 0 H 0 I 0 I o H 0 °Y° A ^NYrN^NYr^NYr -Ayt^nh ^\,NH 0 1 0 1 0 H 0 1 0 YXX>Y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. 0 0 "A ________ 2-n^^nh l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. ^^0 S 0. % 0 0 V HN NH 1 HO' Y ’OH 0 NH 0 . H OH OyO k^^A^N-Y^OH Z O'NH H °n h ? I o TYTn? 0 = H°o\ho A P ' 9 i h o H0\0 0 HN / oh V_ HO 1 DAR Conjugates Antibody (L) X ° o ____An^^nh L--" ' S A % 0 0 V J I > HO-V'-OH O^NHO . H > OH o^o U^Jy^oH / ^x.NH H 0 Ao yQyw f^n^XL °;Hoo^h V P S ' 9 1 H o t HOVo 0 nV / nh2 HO^ X DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. A- ° o ____An^^nh A L— S ex k H9 h r\ o nA0 0VY k z HN^'NH 0 X H0 OH 0H ^X 0 9 1 H HN OH X j 0H 0Y0 MF^n^oh kooh > rxH HXj h ? i o fttn? xni XNhv< 9 MXt ° = H °0^NH 0^Trr' Ho -X 0° A J oHN_ 0 HOVo 0 xNHrM V H °H0J OJ DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L- r ° o _________An'^Anh I 0 S Ck L h2n h r\ 0 o V °VX 1 / Ho'K°y°\pN 0 hny° I H0'” V'°H 0 NH 0 . H HN' / 0H °y° CAnY<ny~oh J>ooh I O'NH H° n h ? I O <Xo o - H o okNH xT Lp 9 o™ o v ho<ho 0 A'Vn'S J H °J °y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. 0 I 0 I 0 I 0 I 0 / 'n"Yn'^n^n'^'n"Yn^n^n'^1'n"YNH2 0 1 0 1 O 1 O 1 O 1 O 0 H °Vy_——— ’ L J L A 1 n m m / ---L y HO'- 'OH T N O n « < A OH O_O H 0 0 W“A x yDAR 9 h o h 9 h 9 H 0 0 O^NH H o H 0 H q H q H hoA / Vx I ox "" H0 I J lii 0 h Vv—-— hct y ‘'oh xA^N^°^^o^N'n^^NX 0H 0^0 H 0 0 O'^H \P < HOVO y -—L DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; Conjugates Antibody (L) 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. OyNH H o H o H q H q H § __L J HoW a h°'y-oh^th ° > XX.'NH o 1 ho’H 1 - DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) H Q Q|_| r n u 'o CX / NH 0 0 1 HO-\"°Y°^A1 o H >1 HCC Y "'OH OH 0^0 H 0 0 > | yynh 'YjcScm0 Y o HOtt J ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. J O^NH 1 0 1 0 1 0 1 0 1 0 ho^^°y°~yi ? h —— HOV'OH 0~NTC-V I OH OyO H 0 0 > O'^H XXXn~? Y / ° HOVo J - DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7- 1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; Conjugates Antibody (L) 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. C O । O । O H O । O 0 NH 1 0 H 0 1 0 1 0 H 0 0 1 ho^oY°~A]) 9 h °YA--------- ’ L hoMoh - J OH OyO H O o t I <VNH ( xAcn- / \,o HOVo V JDAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7- 9EL; 12) L is PTK7-10; Conjugates Antibody (L) 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. A HO ~"\ I O nJCX / JH I o '° 0 = H o °yNH H 0 >0 n"x-oh / NH O 1 H I / Os / V A 9 1 o z 1 HO^Y°Z°~Ti] 9 H [ HO' Y oh Z N o T 1 OH °y° H 0 0 O'NH Z / 0 I HoA« J V y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) HO [ O. N^n\,NH2 ) -d fl H J i^O 0 i H 0 °yNH qATAJ H Q >° ^yNy'Nd-0H NH 0 1 H / V ) ho^oy°~Yi 9 h f hoMoh —----- OH 0^0 H 0 0 L P I H0T\ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— 0 9 ex % A o 9 r H0 IX hn^'nh W O^NHO n 0 O_O k H OOH > O^NH \^o 1 / NyA / O*S 1 A o^nA , < "Hd y DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates DAR Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; Conjugates Antibody (L) 13) L is PTK7-11; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— ______An^^nh o. S o q ^^>0 HNJ^A-'NH HO'"'OH CA _ °H l°Y° 0 H o H 0 H 0 H0 cAnh | 'V^0 O'S 1 J. 0^N"\ J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. Conjugates Antibody (L) L— Q.____k^NH % 0 0 X° HNX^yMH HO-'V'OH O^NH 0 , H OH OyO CANJyN^~OH H o )=0 Y^° । o = H o A-nh I I O ? 0 ? 1 C? h 5 Ah2 onY ho < XQ , . / n-\ / A h y^s= / > "° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14. L— o 0 _______An^^nh S 0^ % HXCo / r OH 0^0 ^H 9 1 H Ho Xo X, CW w T / 1 0 = H 0 Wh 1 zNyV 0 o ' OANA - H O J < H0 , < / N-\__( / 7 J K_ h r\== / HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ll; Conjugates Antibody (L) 14) L is PTK7-12; 15) L is PTK7-13; or 16) L is PTK7-14.
[00261] In alternative embodiments, specific conjugates of Table B are also envisioned with no stereochemistry. Table B-R: Specific Conjugates of the Disclosure Conjugates Antibody (L) L— o o ________An^^NH 0. % 0 o V HN^y.NH > H°'" m °H °^NH 0 ,0 T H o < J hoV^ DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L- 0 O l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. % 0 0 ho^V0^ HN^yn < 0 Hj oy 0 H 0 H o H0 H0 YXiw < J HTo DAR Conjugates Antibody (L) L— -- % 0 0 S*0 HO^Y°yO'Yl V HO'XOH" i 0 OyO q 1 0 1 0 1 0 1 0 ^.»NH YXX>a° F N’ 0 ) H0*W x0 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L 0 0 'A __A N N H ^^0 S Ck % . o o H0^0 0 HN^'™ V Hor y ^ohXAX crisT । 0 । o । 0 । o । 0 f OH 1vN^n^nPn^n^n^nvA ^n^aNH2 °Y 0 o 1 o 1 0 1 o ^»NH ww F }r~\ V A b J H0*W 0 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L- ° 5 -----^NH C 1 CL O O S*° < hoA'0^0^] HoV'-huW o^NH I o 1 o 1 o I o I o " Cy4 < Xaj3ho J > DAR X O l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L- 0 X --An^^nh Ck % 0 0 V hn^-nh HO' '0H Cr NH 1 0 1 0 1 0 1 0 1 0 lYw H°0 D AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L- ° H ----- S 1 0 0 hn^Y^h O^NH ,0 H 0 ,0 ,0 H 5 Y A A 5 H i A / \ ,'NH XXYY F N Y\ A— —( 0 ho*Ho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L- r 1 °> I oh o^nh । o H o | o । 0 H g > y 0 1 O 1 0 0 1 0 ,.^NH 'x5cX)N~f —\ 0 < hoY J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. C ° s L ____An^^nh '"S s CL % 0 0 S*° J HO'Y'OH CT NH 0 I h V A 0H 1 <AmJLn^oh > ] °Y Ho >0 [ <VNH A'i1 H 9 I rA XL o ^L'LnXL LllN-f O = H O ANH F^N^Q^ ° O , H o 5-° / Mt In, A ho-H o H 5 HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L— ° 0 -------An^^nh W S 0. % 0 0 A*0 HoACOYO^H1 hn^-nh HO'Y'OH Uv cAhO , H 0H O^O K^N^OH xx.'NH y-N h o । r-\ 11 AlK 0 - H 0 „A-NH y) "XX,J3j a H°tl O V NH2 HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— ° 1 K _ 0. L h O ° o v HoKoy0^^ HN^y.,NH 0 HN-A H°'A'0H KO o^NH 0 . H O 0H x kA., / CNy^)H ^oh °V° H A° / ' f <\..NH / ~N H Q 1 r"\ ^NV° fl VAnACAfN. / I o / 0 o I i H A Jl <anhS-a,j WK ' ’A Zo ”^o »0 &VrA5 v_ H0 A DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— ° 0 ’"x - U h2n H rA □ o a ay y Ho^royo'vA 0 hnV3 HO1' Y'OH AA> O^NH 0 , H HN' A \ 0H ' CAXmAOH k0H > °Y° ho >0 rf° r / A H 0 . Y\ VNyO rji v.ynan\nJ Jnh°U % FXXjQ-? 0 = H °oTo ..... F N Ih <-V 0° A? oHYo YYVrd HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) H ° H O H 0 L-- H 0 H O X J x L A 0 o V3 ( hn^'^ HO' Y ’OH XX^1 cAn' 1 O 1 0 o 0 0 °h i OyO 0 1 0 1 0 1 0 yy .NH YXXnx° V. hoX{ J l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L— N=N / =\ yy 0 0 A % CL % 0 o X° h0VY°"^ hnK^.-nh HCrY'OH UV o^N- o 1 Q 1 0 1 0 1 0 0H 1 Oyd o 1 o 1 o 1 o o nw p \ H0<~4 y '■ [ )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L-—. 0 0 S CL % CL % \ 0 0 V / HoVr°^n h°^h ; i 0 9aaaaaaaax °yu o 1 o 1 o 1 o 1 o ^X^NH XXXW 1 Vj-A X \P / x c IAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. o o "x s CL % 1 0 0 < HoV^y, hn^'nh < HO'V'OH o ,o | 0 | 0 1 9 < 0H o ^SyNH 0 nY'H° V- 7 HOTy x DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. H ° H O H 0 L--nJ-nVXNYAH H o H O X A ? . . o X° / HO n n hn^nh HO' T 'oh LXX O^NH 1 O 1 O 1 O O O OH i ■■ N J xx N J-zv N / J- .^N A N A o^o o H o H o H o Ho .NH XlX>x° V ho-H; J DAR 0 Op 1 HO VY^n 0 < HO'V'OH UC-nVynh h AX A OH i H I „ 0 cAn | 0 I 0 1 0 1 0 1 O Th YY 0 1 0 1 0 1 0 1 0 YxXAx0 \P < H°Vo -L DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. --L 0 0 0 A HO''Sr 'OH H 4- / > OH i H X 0 ( O N । 0 । 0 । 0 । 0 । 0 <>'NH 0 1 0 1 0 1 0 1 0 yyxw "°o DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. A" 0 A L------ 0 S 0 0 0 V A hn^ / / ™ V A L J L X j 1 / HO' Y 'OH O^NH I 0 u 0 1 o । 0 u 0 Au • 1 I II n || 1 || 1 || H 11 OH £ k N A. / --. N A. / --. N A. / --. N A. / --. N A-. O.-..A ^jf 1 0 1 0 1 0 0 1 0 / \AH V F N YX DAR HO^O l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. S' o 0 ____I ---- ' ^""Sd 0. ° 0 J AVy. hn^nh 1 >. HO' Y ,QH O^NH 1 0 1 0 1 0 1 0 0^0 II 1 II H II 1 II H II o io o io 0 / X,..'NH ho / 4 > dar l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Z" ° o y^N^^NH A L S CL L h9 h n 0 o Ao oUy n H°VXOxrN hn^'NH 0 7 H0'V’OH Uy U 0 . H hn'U y i - UU^on Uooh u v hVnu o . o cLo Tyry0 ‘ U'" f^nA U t o । A oHrU \C° A' Anh / u HOU 7J H U NO V_ \ o ho U DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. C O I O I O I O I 0 0 OyN^ 1 0 1 0 1 0 1 0 1 0 0 o °V\ _____ ---L l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. ^hW^o-^ / 8- 1 J OH ? H 0 0 A OyO ~XXXn- / P HO-W J DAR Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. OyNH H o H 0 H q H o H __L 5 hoaw ° > O'NH XXXN^f p H0<° ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) H Q, Q|_| r T ° 'o CK / NH 0 0 1 0 H 0YA J HO'" Y "'oh \ OH or6 0 0 y / \.NH XX^Oy0 , ho*f\ J x0 ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. 0 OyNH 1 0 1 0 1 0 1 0 1 0 HoW [j5] 0 H °V\----- HoVoH I OH 1 H 0 0 > ^.xNH F - H°^° ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. 9 H ? h o h o H O o ovnh 1 O 1 o 1 0 1 0 1 o Ho^Y°Y°'^k o h °y-\ ___ ---L l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. HO' y^OH y OH ! H 0 0 1 °Y° O'NH 'XXXn^L p L hoVo J DAR Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. 0 । 0 h 0 | 0 h / ^nAV^nV^nV^oh Q NH 1 0 1 0 1 0 1 0 o H °V\ -------L ) HO”'Y''OH >. OH 1 H 0 0 Oyd H°Vo J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. HO J fl HO n ' o 0 = H o °yNH Aid H Q >0 f^YNY'N'^V-0H 7 Oy / k ) Hod°y°'~A 0 H °V\__ ( hoV'oh --------—L ™ or6 H 00 O'NH XXX)d < d > DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— 0 I o. 0 X 0 O^NH 0 on 1 AA & \ OyO bS'.0H V AyN^ ( O^NH XX"0 1 zN<zV oA । A OXX X? f ,-X \ / NA_f 7 / — . _ < H„X A DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L— 0 u "A --A N N H Ck o 0 0 A0 H0Vr°'^n hn-*— HO' T 'OH 0J MH 0 / 0H 1 k A o P । °Y° h 0H V \ -¼ ( O^NH \A,o 0 1 cAn^\ A HO J l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L-- A S 0. % 0 0 A0 HcAr°y0^ hn^^-nh HO'” Y^OH nA n 0B °A As-'Nx. / CT NH ^<V° 0*1 1 1 0^N"\ - Ai / / n-\A / J H0 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— C ° ? ______An^Anh A s ex o q HcA / V0^^. Her Y 'OH OA „ „ n n °" x i (j nh 0 ] . <o X_ Hho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L— 0 0 s 0. % 0 o HO'"Sr 'OH O^NH 0 . u 0H ' CAI NT® oy° nt V' 0 NH 0 - H o h^NH \ / ^0 ° n frVAC 0*3 H 0 J 1 J HO I 0^N"\ / nA—-A hho DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— r _______An^^nh S ex % h°XCw\t OH i NH 0 . H 0^6 1—^A^n^oh ^yn- h ° / ~5 h 9 I rA O^NH ^VY^N'S^Y 0 = H o „Anh Yr 1 0 A „ 1 zNxA / r o . H 0 ?y 0¾^ < A.o J h r\A HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Table B-S: Specific Conjugates of the Disclosure Conjugates Antibody (L) L— _____A_____Q T o. P C / E d ° ZI r°r° ^-J~° o-? °yC& A V2 i O / --\ I / LL o >o o=< b O 32 T l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; Conjugates Antibody (L) 15)LisPTK7- 13; or 16) L is PTK7-14. C o o | --—S L °> J L X T / x o ho^A / ^oh f I AcHN XQ TYVW HO>^OH A 0 AcHN V ho<X ho^AAoh k \ 0 V AcHNV ] ' -X DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L- -- % 0 0 V h°V-oh^Y o OyO q 1 0 1 0 1 0 1 0 XoCm0 p J H0*W x0 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L- r 0 0 l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. °> % 0 0 V I hoYy0^ hn^nh > H0' Y °H oA.H I 0 1 0 1 0 1 0 | 0 | YXXW H^° DAR Conjugates Antibody (L) L- 0 II —-----H, S | 0 h°'Y'oh M-J A ,o H o ,o ,o H 5 Y A A 5 H i A / \ ,'NH XXX / yL F N Y\ A— —( 0 ho*Ho ~[ DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— ------ 0. HCXo vo x V l l Yr il HO'' iT *'OH ^s. Jk Us. OH | ° 1 ft H ft 1 9 1 ft H ft oj ^n^nh J 0 1 O 1 0 0 1 0 / \.-'NH YuaQnAL \ 0 -- DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L----- -- 0 O 0 JL 2 r “ hn^Vh HO''^f''OH k JL J 1 oh 0 I 2 I 2 | 2 | 2 k- 0 ‘ Y £ S H 5 । J H S ^NH XXkN- / —\ o < HOpo J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— I Q q )=o k & . W? Q ° ° v X Q IZ IZ O=^~ VO >o IZ TO= / ^ O ZI >=O , Z . \ I / K M ✓ O-----Y----- 7) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. H ° H O H ° L N^N^yN^N^N^NH H o H O X X \ x A o ° Y° / ,'NH HO' Y 'OH XX> O^N' । 0 0 O | 0 0 OyO Q o 1 0 1 0 1 0 J J J F V hoV J l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L— N=N / =\ yv o / A—n^Anh 0 0. % % 0 0 S*0 H° HN^'NH HO' i^^OH Amz । n । O i 0 i 0 i 0 - if vxxxxa OyO 0 1 0 1 0 1 0 0 ^\.NH F n iA \o \ HO*t~v y '° [ )AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L—- 0 0 S % CL % \ 0 0 V / hows^i h°M°h X o XAAAAAX °yu o 1 o 1 o 1 o 1 o ^X^NH XXXW I F^^N V>A x. y" p / '° IAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. q o "x s 0 % Io o 'v0 < HO^y0^ hn^'nh < | 0 XAAAAAAAAXf °y° o io 1 o 1 o 1 o XXj3k° i F Nvh \~P 7 HOTy x DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. H ° H O H ° L N-X-NzyN^AN--yNX'NH Hq H O k] X -= \ X A o „ o X° / HO xXxx ™^NH Ho” T 'OH kXX oXh I O I O I 0 1 0 1 o OH 1 N J, x-, N A / ■.. N J- z-, N X. <- . N J-. 0^0 O H 0 H 0 h o H 0 ^.NH yW^ P 11 f N-X F N^L}x V hoXX J DAR 0 On X Uy^y-H H * c / y I 0 1 0 1 0 1 0 1 0 Ju SrN^N^N^N^N^N^N^N^N^0H XX'^ o 1 0 1 0 1 0 1 0 0 J J J N~C P X ho-H __L DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. ? n 0 9 P J HO'V y 0 k ■s > 1 0*y । 0 । 0 । 0 । 0 । 0 <>'NH 0 1 0 1 0 1 0 1 0 1ZXn^° H0<° DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) A o o „ ? P HO'" yKh VWnW'yNH H £ / OH I H A— 0 txiw p < HOVo J D -L AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. o 0 0 hcA / V \^n 0 °Vo^°^nA^nV^^ ho''V‘"oh U^n^tnh h OH 1 H K nx 0 ^¼¾¾841 , WK a KIp J hoTA X D -L AR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L--- ze i Q Q 7=° x o / \ 7* / =( Z —■ O J~Z , 25 ° ? off >O / 'XV° 5° ° ° V Z O- P 'U>.^ d ° ZE u v 73 l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. A 0 ? "A 0 S 0 0 0 V y hoY / vn hn'1—y \ L J 1 if j J f HO' Y 'OH O^NH । 0 0 । 0 i 0 0 OH 1 Ln JL N JL N JL N JL N JL 0 0 ^^OH ] 0 1 0 1 0 0 1 0 „»NH V F N^yf} DAR Hoyt l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. S' o 0 ____I ---- ' ^""Sd 0. u 0 V ) hoVZYn hnA^-.'NH 1 < <XX LI J 1 V N HO Y OH O^NH i 0 i 0 i 0 i 0 / 0H o I | 0^0 II 1 II H II 1 II H II Y o io o io o / X,..'NH kXXX I P H Yo > DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Z" ° o y^N^^NH A L S CL L h9 h n 0 o Ao oUy n H°VXOxrN hn^'NH 0 7 H0'V’OH Uy U 0 . H hn'U y ) 1 UVu U=ooh r 0Y° HVnU o . q CLo Tyry0 ‘ U'" f^nA U t o । A oHrU \C° A' Anh / u HOU 7J H U NO V_ \ o ho U DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. C 0 1 0 1 0 1 0 1 0 ^N^NA^NA^NA^N^yOH 0 OyN^ 1 0 1 0 1 0 1 0 1 0 o u V\____ ---L l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. HO' T OH I N 0 Y X J OH 1 H 0 0 A OyO O'^H ~XXXn^L P HO-W J DAR Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. OyNH H 0 H 0 H q H Q H q __ QI o _———■— ho^Y°VO Im 9 h V\_—■—— < HO' Y 'OH T H Jo > A OH OyO U z O'NH Y / ° H0<° ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) H Q, Q|_| r T ° 'o CK / NH 0 0 1 0 H 0YA J HO'" y"'oh \ OH oro o o y / \.NH XX^Oy0 , ho*f\ J x0 ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. J J. 0J O^NH 1 0 1 0 1 0 1 0 1 0 HoW [I5] 0 H °V\----- HoV'OH 1 OH 1 H 0 0 > ^.xNH F - H°^° ^DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. 9 H ? h o h o H O o O^NH 1 O 1 o 1 o 1 0 1 5 HO^OyO^l o H V\____ ---L l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. y OH | H 0 0 1 °Y° O'NH 'XXXn^L p L hoVo J DAR Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. 0 । 0 h 0 | 0 h / ^nAV^nV^nV^oh Q NH 1 0 1 0 1 0 1 0 o H °V\ -------L ) HO”'Y''OH V >. OH | H 0 0 OyO H°Vo J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. HO J fl HO n ' o 0 = H o °yNH Aid H Q >0 f^YNY'N'^V-0H 7 Oy / k ) Hod°y°'~A 0 H °V\__ ( hoV'oh --------__L ™ orl H 00 O'NH XXX)d < d > DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— 0 9 "A ____________An^^nh o. A 9 n A° A o A 9 । H01 j hn^-nh HO'” Y OH „AKIU r> OH 0 ,o 0^0 / 'OH V ( O^NH oA । J. O^NA A? .-\ Z' NA- / ? / — A hho " DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) L— 0 9 ~A ____________An^^nh S °> A o o A H0 IT "TiT hn-^'™ H0' 'OH AAJ cAnh 0 OH | L / X 0 -P 0^0 '.S'- V I 7 H o UH AyN^ A oAh \A^o 0 1 O^N^ I <M2 A HO J DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7-12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— 0 0 A s 0 % 0 o A0 hn ” ““ LI 0 7¾¾¾¾1¼ cr nh VY° Ay-k / 0 1 1 1 < Al0 ,- / N-x / y J H0 DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7- ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. L— ° 11 ______An^^nh A s A o 0 HOWVl HN^Y'NH H° OH °H °NH|O | 0 | 0 | 0 1 Q A^, ( cAnh yCo oA 1 1 < h r\=J / HO DAR l)LisPTK7-l; 2) L is PTK7-1EL; 3) L is PTK7-2; 4)LisPTK7-3; 5) L is PTK7-4; 6) L is PTK7-5; 7) L is PTK7-6; 8) L is PTK7-7; 9) L is PTK7-8; 10) L is PTK7-9; ll)LisPTK7-9EL; 12) L is PTK7-10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14. Conjugates Antibody (L) ll)LisPTK7- 9EL; 12) L is PTK7- 10; 13)LisPTK7-ii; 14) L is PTK7- 12; 15)LisPTK7- 13; or 16) L is PTK7-14.
[00262] Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 1 to about 8. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 2 to about 8. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 2. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 3. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 4. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 5. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 6. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 7. Conjugates of Table B, Table B-S, and Table B-R, each independently have a DAR of about 8.
[00263] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
[00264] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
[00265] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
[00266] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, nC, 13C and / or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
[00267] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.
[00268] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, nC, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S,35S, 36S, 35C1,37C1, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[00269] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
[00270] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chern., 1981, 64(1-2), 9-32.
[00271] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
[00272] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
[00273] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
[00274] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
[00275] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.
[00276] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
[00277] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
[00278] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.
[00279] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Targeting Unit (L)
[00280] In some embodiments, for a Drug-Linker or salt of Formula (I), Formula (I-A), Formula (la), Formula (LAAa), Formula (lb), Formula (I-AAb), Formula (I-AA), Formula (I-AB), Formula (I-B), Formula (II-A), Formula (II-B) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6) Formula (A-7), or Formula (A-8), the Targeting Unit is selected from an antibody or an antigen-binding fragment thereof. In some cases, the Targeting Unit is selected from a group consisting of chimeric antibodies, humanized antibodies, and human antibodies. In some cases, the Targeting Unit, performs a targeting function. In some cases, a Targeting unit specifically binds to a target molecule. In some cases, specifically binds refers to the ability of a Targeting unit (e.g., an antibody or portion thereof) described herein to bind to a target with a KD 10'5 M (10000 nM) or less, e.g., 10'6M, 10'7M, 10'8M, 10'9M, 10'10M, 10'11 M, 10'12M, or less. In some cases, a Targeting unit is said to specifically bind to its target when it preferentially recognizes its target in a complex mixture of proteins and / or macromolecules.
[00281] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the Targeting unit is an antibody or antigen binding portion thereof is a bispecific or multispecific binding agent. Bispecific and multi-specific antibodies include the following: an scFvl-ScFv2, an ScFvl 2-Fc-scFv2 2, an IgG-scFv, a DVD-Ig, a triomab / quadroma, a two-in-one IgG, a scFv2-Fc, a TandAb, and an scFv-HSA-scFv. In some embodiments, an IgG-scFv is an IgG (H) -scFv, scFv-(H) IgG, IgG (L) -scFv, svFc- (L) IgG, 2scFV-IgG or IgG-2scFv.
[00282] In some embodiments, for a Drug-Linker or salt of Formula (I), Formula (I-A), Formula (la), Formula (LAAa), Formula (lb), Formula (I-AAb), Formula (LB), Formula (II-A), Formula (II-B), or for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6) Formula (A-7), or Formula (A-8), the Targeting unit is UC-961. In some cases, L is UC-961. In some cases, the Targeting unit is PTK7. In some cases, L is PTK7.
[00283] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6) Formula (A-7), or Formula (A-8), L is an antibody that binds to human protein tyrosine kinase 7 (PTK7).
[00284] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6) Formula (A-7), or Formula (A-8), the Targeting unit is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, L is an anti-PTK7 antibody. In some cases, the anti-PTK7 antibody comprises 8 sulfur atoms that each can independently form a bond with about eight separate drug-linkers via M2.
[00285] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6) Formula (A-7), or Formula (A-8), the Targeting unit is an anti-PTK7 antibody or an antigen-binding portion thereof. In some cases, L is an anti-PTK7 antibody. In some cases, the PTK7 antibody is modified with a group capable of reacting to form M2 (e.g., to form •N ). In some cases, the PTK7 antibody is modified with a group capable of a click reaction to form M2 (e.g., to form N
[00286] In some embodiments, for a Drug-Linker or salt of Formula (I), Formula (I-A), Formula (la), Formula (I-AAa), Formula (lb), Formula (I-AAb), Formula (LB), Formula (II-A), Formula (II-B), or for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6) Formula (A-7), or Formula (A-8), the Targeting unit is a cancer associated antigen such as CD 19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2) , high molecular weight-melanoma associated antigen (HMW-MAA) , MAGE-A1, IL-13R-a2, GD2, lpl9q, ABL1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, JAK2, KDR (VEGFR2) , KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM1, SMO, SPARC, TLE3, TOP2A, T0P01, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RBI, SMAD4, SMARCB1, STK1, MLH1, MSH2, MSH6, PMS2, R0S1, ERCC1, 5T4 (TPBG) , B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, CDH6, CLDN6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3) , EPCAM, FOLRI, IGF1R, IL2RA (CD25) , IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN) , NaPi2b (SLC34A2) , nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, Tissue Factor (TF) , TROP2 or B7-H4.
[00287] In some embodiments, a Targeting unit specifically binds to a target such as CD 19, CD20, CD30, CD33, CD70, LIV-1 orEGFRv3.
[00288] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), L of the disclosed antibody-drug conjugate can be any PTK7-binding antibody. In some cases, the antibody is a chimeric, CDR-grafted, humanized, or a recombinant human antibody, or PTK7-binding fragment thereof. In some cases, the antibody is an internalizing antibody and / or a neutralizing antibody. In some cases, the PTK7 antibody, or antigen-binding fragment thereof, includes one or more CDR(s) of the antibody (such as one, two, three, four, five, or all six CDRs). In some cases, the CDRs are as described elsewhere herein.
[00289] In some embodiments, a human PTK7 polypeptide sequence is available under UniProt Accession No. Q13308 (PTK7_HUMAN) and is shown below: MGAARGSPAR PRRLPLLSVL LLPLLGGTQT AIVFIKQPSS QDALQGRRAL LRCEVEAPGP VHVYWLLDGA PVQDTERRFA QGSSLSFAAV DRLQDSGTFQ CVARDDVTGE EARSANASFN IKWIEAGPVV LKHPASEAEI QPQTQVTLRC HIDGHPRPTY QWFRDGTPLS DGQSNHTVSS KERNLTLRPA GPEHSGLYSC CAHSAFGQAC SSQNFTLSIA DESFARVVLA PQDVVVARYE EAMFHCQFSA QPPPSLQWLF EDETPITNRS RPPHLRRATV FANGSLLLTQ VRPRNAGIYR CIGQGQRGPP IILEATLHLA EIEDMPLFEP RVFTAGSEER VTCLPPKGLP EPSVWWEHAG VRLPTHGRVY QKGHELVLAN IAESDAGVYT CHAANLAGQR RQDVNITVAT VPSWLKKPQD SQLEEGKPGY LDCLTQATPK PTVVWYRNQM LISEDSRFEV FKNGTLRINS VEVYDGTWYR CMSSTPAGSI EAQARVQVLE KLKFTPPPQP QQCMEFDKEA TVPCSATGRE KPTIKWERAD GSSLPEWVTD NAGTLHFARV TRDDAGNYTC IASNGPQGQI RAHVQLTVAV FITFKVEPER TTVYQGHTAL LQCEAQGDPK PLIQWKGKDR ILDPTKLGPR MHIFQNGSLV IHDVAPEDSG RYTCIAGNSC NIKHTEAPLY VVDKPVPEES EGPGSPPPYK MIQTIGLSVG AAVAYIIAVL GLMFYCKKRC KAKRLQKQPE GEEPEMECLN GGPLQNGQPS AEIQEEVALT SLGSGPAATN KRHSTSDKMH FPRSSLQPIT TLGKSEFGEV FLAKAQGLEE GVAETLVLVK SLQSKDEQQQ LDFRRELEMF GKLNHANVVR LLGLCREAEP HYMVLEYVDL GDLKQFLRIS KSKDEKLKSQ PLSTKQKVAL CTQVALGMEH LSNNRFVHKD LAARNCLVSA QRQVKVSALG LSKDVYNSEY YHFRQAWVPL RWMSPEAILE GDFSTKSDVW AFGVLMWEVF THGEMPHGGQ ADDEVLADLQ AGKARLPQPE GCPSKLYRLM QRCWALSPKD RPSFSEIASA LGDSTVDSKP (SEQ ID NO :198) In the above sequence, amino acids 1-30 correspond to the signal sequence; amino acids 31-704 correspond to the extracellular domain (ECD); amino acids 705-725 correspond to the transmembrane domain; and amino acids 726-1070 correspond to the intracellular domain. The PTK7 binders of the conjugates described herein bind to the ECD of PTK7.
[00290] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the conjugate is conjugated to an anti-PTK7 antibody or an antigen-binding portion thereof that competes or cross-competes for binding to human PTK7 with, or binds to the same epitope of human PTK7 as, any one of SLX-1040, Z12, Z23, Z31, SLX-1042, or SLX-1059.
[00291] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the conjugate is conjugated to an anti-PTK7 antibody or an antigen-binding portion thereof that competes or cross-competes for binding to human PTK7 with, or binds to the same epitope of human PTK7 as, an antibody comprising: a) a heavy chain variable region (Vh) comprising the amino acid sequence of SEQ ID NO:76 and a light chain variable region (Vl) comprising the amino acid sequence of SEQ ID NO:75; b) a Vh comprising the amino acid sequence of SEQ ID NO: 178 and a Vl comprising the amino acid sequence of SEQ ID NO: 188; c) a Vh comprising the amino acid sequence of SEQ ID NO: 193 and a Vl comprising the amino acid sequence of SEQ ID NO: 188; d) a Vh comprising the amino acid sequence of SEQ ID NO: 173 and a Vl comprising the amino acid sequence of SEQ ID NO: 188; e) a Vh comprising the amino acid sequence of SEQ ID NO: 112 and a Vl comprising the amino acid sequence of SEQ ID NO: 111; or f) a Vh comprising the amino acid sequence of SEQ ID NO: 128 and a Vl comprising the amino acid sequence of SEQ ID NO: 127.
[00292] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody or antigen-binding portion comprises the HCDR1-3 and LCDR1-3 amino acid sequences of any one of the antibodies exemplified herein. The assignment of CDR regions may be in accordance with any method known in the art, such as IMGT®, Kabat, Chothia, Martin, Contact, or AHo definitions, or any combination of any of these definitions (Kabat plus Chothia, for example). Examples of CDR definitions under different methods are shown below for SLX-1040 (SEQ: SEQ ID NO): SLX-1040 HCDRs Definition HCDR1 SEQ HCDR2 SEQ HCDR3 SEQ IMGT® GYTFTTYW 151 IDPSDSYT 157 LLPAWFGY 161 Kabat TYWMH 149 EIDPSDSYTTYNQKFTG 155 PAWFGY 160 Chothia GYTFTTY 150 DPSDSY 156 PAWFGY 160 AHo KASGYTFTTYWMH 152 EIDPSDSYTT 158 LLPAWFGY 161 Contact TTYWMH 153 WIGEIDPSDSYTT 159 LLPAWFG 162 SLX-1040 LCDRs Definition LCDR1 SEQ LCDR2 SEQ LCDR3 SEQ IMGT® QEISGY 164 AAS 167 LQYATYPFT 170 Kabat RASQEISGYLS 163 AASTLDS 166 LQYATYPFT 170 Chothia RASQEISGYLS 163 AASTLDS 166 LQYATYPFT 170 AHo RASQEISGYLS 163 YAASTLDS 168 LQYATYPFT 170 Contact SGYLSWL 165 RLIYAASTLD 169 LQYATYPF 171 Thus, for example, the SLX-1040 IMGT®-defmed HCDR1-3 and LCDR1-3 sequences of SEQ ID NOs: 151, 157, 161, 164, 167, and 170, respectively, may be replaced in any embodiment described herein by SEQ ID NOs:149, 155, 160, 163, 166, and 170, respectively; SEQ ID NOs:150, 156, 160, 163, 166, and 170, respectively; SEQ ID NOs: 152, 158, 161, 163, 168, and 170, respectively; or SEQ ID NOs: 153, 159, 162, 165, 169, and 171, respectively. Also contemplated is a set of SLX-1040 CDRs wherein each of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 may individually be specified according to any of the methods for defining SLX-1040 CDRs as shown above (e.g., HCDR1 specified by the Kabat definition, HCDR2 specified by the Chothia definition, etc.). The same means for defining SLX-1040 CDRs are contemplated for any of the exemplified antibodies herein.
[00293] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody or antigen-binding portion thereof has: - an HCDR1 selected from SEQ ID NOs: 149-154; - an HCDR2 selected from SEQ ID NOs: 155-159; - an HCDR3 selected from SEQ ID NOs: 160-162; - an LCDR1 selected from SEQ ID NOs: 163-165; - an LCDR2 selected from SEQ ID NOs: 166-169; and - an LCDR3 selected from SEQ ID NOs: 170 and 171.
[00294] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody or antigen-binding portion thereof has HCDR1-3 andLCDRl-3 comprising SEQ ID NOs:151, 157, 161, 164, 167, and 170, respectively. In some embodiments, the anti-PTK7 antibody or antigen-binding portion has HCDR1-3 andLCDRl-3 comprising SEQ ID NOs: 154, 155, 161, 163, 166, and 170, respectively.
[00295] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody or antigen-binding portion has HCDR1-3 and LCDR1-3 comprising SEQ ID NOs:204, 209, 213, 216, 219, and 222, respectively.
[00296] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody or antigen-binding portion has HCDR1-3 and LCDR1-3 comprising SEQ ID NOs:226, 231, 235, 238, 241, and 244, respectively.
[00297] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody comprises an HC amino acid sequence comprising SEQ ID NOs:76 and 201, optionally without the C-terminal lysine, and an LC amino acid sequence comprising SEQ ID NOs:75 and 199.
[00298] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody comprises an HC amino acid sequence comprising SEQ ID NOs: 178 and 201, optionally without the C-terminal lysine, and an LC amino acid sequence comprising SEQ ID NOs: 188 and 199.
[00299] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody comprises an HC amino acid sequence comprising SEQ ID NOs: 193 and 201, optionally without the C-terminal lysine, and an LC amino acid sequence comprising SEQ ID NOs: 188 and 199.
[00300] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody comprises an HC amino acid sequence comprising SEQ ID NOs: 173 and 201, optionally without the C-terminal lysine, and an LC amino acid sequence comprising SEQ ID NOs: 188 and 199.
[00301] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody comprises an HC amino acid sequence comprising SEQ ID NOs: 112 and 201, optionally without the C-terminal lysine, and an LC amino acid sequence comprising SEQ ID NOs: 111 and 199.
[00302] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody comprises an HC amino acid sequence comprising SEQ ID NOs: 128 and 201, optionally without the C-terminal lysine, and an LC amino acid sequence comprising SEQ ID NOs: 127 and 199.
[00303] In some embodiments, for a conjugate or salt of Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8), the anti-PTK7 antibody of the present disclosure can be an IgG, an IgM, an IgE, an IgA, or an IgD molecule, but is typically of the IgG isotype, e.g., of IgG subclass IgGl, IgG2, IgG3 or IgG4. In some embodiments, the antibody is of the isotype subclass IgGl. Making of PTK7-Binding Proteins (e.g., anti-PTK7 antibodies and proteins comprising the antibodies or antigen-binding portions thereof)
[00304] The PTK7-binding protein of the present disclosure may be produced recombinantly using isolated nucleic acid molecules such as expression constructs. The coding sequences for each polypeptide chain may be cloned into a single vector or cloned into separate vectors (e.g., a pair or set of vectors). The proteins may be produced in host cells, e.g., mammalian host cells, using appropriate expression constructs. Mammalian cell lines available as hosts for expression include, without limitation, Chinese hamster ovary (CHO) cells, NS0 cells, SP2 cells, HEK-293T cells, 293 Freestyle cells (Invitrogen), NIH-3T3 cells, HeLa cells, baby hamster kidney (BHK) cells, African green monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and A549 cells. Other cell lines that may be used are insect cell lines, such as Sf9 or Sf21 cells, and yeast cell lines. In certain embodiments, the cell lines are not derived from a human embryo. Cell lines may be selected based on their expression levels.
[00305] Host cells used to produce the PTK7-binding proteins are “recombinant host cells.” A “recombinant host cell” (or simply “host cell”), as used herein, means a cell into which a recombinant expression construct has been introduced. By definition, a recombinant host cell does not occur in nature. A protein produced from a recombinant host cell is a recombinant protein.
[00306] The PTK7-binding protein may be isolated and purified from the host cell culture using well known methods, such as centrifugation; ultracentrifugation; protein A, protein G, protein A / G, or protein L purification; and / or ion exchange chromatography. Pharmaceutical Formulations
[00307] Provided herein, in certain embodiments, are pharmaceutical compositions comprising a therapeutically effective amount of a Drug-Linker or salt of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (I), Formula (LA), Formula (la), Formula (I-AAa), Formula (lb), Formula (I-AAb), Formula (LAA), Formula (I-AB), Formula (I-B), Formula (II-A), Formula (II-B), or a conjugate or salt of Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII), Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5), Formula (A-6), Formula (A-7), or Formula (A-8) (also referred to herein as “a pharmaceutical agent”).
[00308] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).
[00309] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.
[00310] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
[00311] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.
[00312] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
[00313] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
[00314] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
[00315] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.
[00316] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
[00317] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.
[00318] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.
[00319] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
[00320] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
[00321] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
[00322] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.
[00323] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
[00324] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
[00325] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example,jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
[00326] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
[00327] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
[00328] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises watersoluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
[00329] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
[00330] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
[00331] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition. Methods of Treatment
[00332] In an aspect, the present disclosure provides a method of treating a subject with a tumor. In some cases, the treatment of a subject with the tumor includes administering to a subject in need thereof a Drug-Linker or salt of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (I), Formula (I-A), Formula (la), Formula (I-AAa), Formula (lb), Formula (LAAb), Formula (I-B), Formula (ILA), Formula (II-B) (which further comprises a targeting unit), or for a conjugate or salt of Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII), Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5) Formula (A-6), Formula (A-7), or Formula (A-8), or a pharmaceutical composition of any one thereof. In some cases, the tumor is associated with a cancer. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers. In some cases, the cancer is small cell lung cancer. In some cases, the cancer is large cell lung cancer.
[00333] In an aspect, the present disclosure provides a method of treating a subject with a cancer. In some cases, the treatment of a subject with the cancer includes administering to a subject in need thereof a Drug-Linker or salt of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (I), Formula (I-A), Formula (la), Formula (I-AAa), Formula (lb), Formula (I-AAb), Formula (I-B), Formula (ILA), Formula (II-B) (which further comprises a targeting unit), or a conjugate or salt of Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII), Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5) Formula (A-6), Formula (A-7), or Formula (A-8), or a pharmaceutical composition of any one thereof. In some cases, the tumor is associated with a cancer. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers. In some cases, the cancer is small cell lung cancer. In some cases, the cancer is large cell lung cancer.
[00334] In some embodiments, compounds described herein can be used for treating diseases such as, but not limited to, hyperproliferative diseases, including: cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma; intestinal cancers, particularly colorectal cancer; ovarian cancer; small cell and non-small cell lung cancer (SCLC and NSCLC); breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomysosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; leukemias such as acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML); neoplasms of the central nervous systems, particularly brain cancer; multiple myeloma (MM), lymphomas such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma. Clinically, practice of the methods and use of compositions described herein will result in a reduction in the size or number of the cancerous growth and / or a reduction in associated symptoms (where applicable). Pathologically, practice of the method and use of compositions described herein will produce a pathologically relevant response, such as: inhibition of cancer cell proliferation, reduction in the size of the cancer or tumor, prevention of further metastasis, and inhibition of tumor angiogenesis. The method of treating such diseases comprises administering a therapeutically effective amount of an inventive combination to a subject. The method may be repeated as necessary. The cancer can be renal, lung, gastric, or ovarian cancer.
[00335] In some embodiments, the treatment of tumor-bearing subjects inhibits tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject, which is typically a human but can be another mammal.
[00336] In some embodiments, compositions described herein can be administered in combination with other therapeutic agents, including antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include adalimumab, ansamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribin, cytarabin, cryptophycins, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferons, interleukins, P-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, and vindesine.
[00337] The Drug-Linker or salt of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (I), Formula (I-A), Formula (la), Formula (I-AAa), Formula (lb), Formula (I-AAb), Formula (LB), Formula (II-A), Formula (II-B), Formula (II-C), Formula (II-D), Formula (II-E), Formula (II-F), or a conjugate or salt of Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII), Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5) Formula (A-6), Formula (A-7), or Formula (A-8), can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
[00338] The Drug-Linker or salt of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (I), Formula (I-A), Formula (la), Formula (I-AAa), Formula (lb), Formula (I-AAb), Formula (I-AA), Formula (LAB), Formula (I-B), Formula (II-A), Formula (ILB), Formula (ILC), Formula (II-CA), Formula (ILD), Formula (ILE), Formula (ILF), Formula (II-G), or a conjugate or salt of Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII), Formula (A), Formula (Aa), Formula (Ab), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (A-5) Formula (A-6), Formula (A-7), or Formula (A-8), described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
[00339] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
[00340] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
[00341] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a longterm basis upon any recurrence of symptoms.
[00342] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
[00343] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Nonlimiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
[00344] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
[00345] In certain embodiments, the invention provides a method of treating or preventing a disease, state, or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein. Preparation of Drug-Linkers and Conjugates of the Disclosure
[00346] The Linkers, Drug-Linkers and conjugates of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis.
[00347] In some embodiments, Linkers, Drug-Linkers and conjugates of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. In some embodiments, a conjugate may be prepared by several routes employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group of a Targeting unit (e.g., an antibody or antigen binding portion thereof or non-antibody protein scaffold) with a bivalent Linker to form a Targeting unit-Linker intermediate via a covalent bond, followed by reaction with a Drug; and (2) reaction of a nucleophilic group of a Drug with a bivalent Linker, to form Drug-Linker, via a covalent bond, followed by reaction with a nucleophilic group of a Targeting unit.
[00348] In some embodiments, techniques for attaching a drug to Targeting units (such as antibodies or antigen binding portions thereof or non-antibody scaffolds) via linkers may be used. In some cases, a Linker is first attached to a Drug (e.g., a cytotoxic agent (s), immune modulatory agent or other agent) and then the Drug-Linker (s) is attached to the Targeting unit (e.g., an antibody or antigen binding portion thereof or non-antibody protein scaffold). In some cases, a Linker is first attached to a Targeting unit (e.g., an antibody or antigen binding portion thereof or non-antibody protein scaffold), and then a Drug is attached to a Linker.
[00349] In some embodiments, a Drug is attached to a Targeting unit via a Linker in a manner that reduces the activity of the Drug until it is released from the conjugate (e.g., by hydrolysis, by proteolytic degradation or by a cleaving agent.
[00350] In some embodiments, nucleophilic groups on Targeting units such as antibodies, antigen binding portions and other binding agents (including non-antibody scaffolds) include, but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated. Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on Linkers including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; and (iii) aldehydes, ketones, carboxyl, and maleimide groups. In some cases, targeting units, such as antibodies (and antigen binding portions and other binding agents (including non-antibody scaffolds)) have reducible interchain disulfides, i.e., cysteine bridges. In some cases, antibodies (and antigen binding portions and other binding agents (including nonantibody scaffolds)) may be made reactive for conjugation with Linkers or Drug-Linkers by treatment with a reducing agent such as DTT (dithiothreitol) or tricarbonyl ethylphosphine (TCEP), such that the antibody is fully or partially reduced. In some cases, each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. In some cases, additional nucleophilic groups can be introduced into Targeting units such as antibodies (and antigen binding portions and other binding agents (including non-antibody scaffolds)) through modification of lysine residues, e.g., by reacting lysine residues with 2-iminothiolane (Traut's reagent), resulting in conversion of an amine into a thiol. In some cases, reactive thiol groups may also be introduced into a Targeting unit (such as an antibody and antigen binding portions and other binding agents (including non-antibody scaffolds)) by introducing one, two, three, four, or more cysteine residues (e.g., by preparing antibodies, antigen binding portions and other binding agents (including non-antibody scaffolds) comprising one or more non-native cysteine amino acid residues).
[00351] In some embodiments, conjugates may also be produced by reaction between an electrophilic group on a Targeting unit, such as an aldehyde or ketone carbonyl group, with a nucleophilic group on a Linker or Drug-Linker. In some cases, useful nucleophilic groups on a linker reagent include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxyl, and arylhydrazide. In some cases, an antibody (or antigen binding portion thereof or other binding agent (including non-antibody scaffolds)) is modified to introduce electrophilic moieties that are capable of reacting with nucleophilic substituents on a Linker or Drug-Linker. In some cases, the sugars of glycosylated antibodies may be oxidized, e.g. with periodate oxidizing reagents, to form aldehyde or ketone groups which may react with the amine group of a Linker or Drug-Linker. In some cases, the resulting imine Schiff base groups may form a stable linkage, or may be reduced, e.g., by borohydride reagents to form stable amine linkages. In some cases, reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium meta-periodate may yield carbonyl (aldehyde and ketone) groups in the antibody (or antigen binding portion thereof or other binding agent (including non-antibody scaffolds)) that can react with appropriate groups on the Linker or Drug-Linker (see, e.g., Hermanson, Bioconjugate Techniques).
[00352] In some embodiments, exemplary nucleophilic groups on a Drug, such as a cytotoxic agent, include, but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxyl, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on a Linker including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups, ultimately forming a Drug-Linker or a conjugate.
[00353] In some embodiments, a Linker or Drug-Linker is attached to an interchain cysteine residue(s) of an antibody (or antigen binding portion thereof or other binding agent (including non-antibody scaffolds)). In some cases, the Linker or Drug-Linker typically comprises a maleimide group for attachment to the cysteine residues of an interchain disulfide. In some cases, a Linker or Drug-Linker is attached to a cysteine residue(s) of an antibody or antigen binding portion thereof.
[00354] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein.
[00355] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLES
[00356] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile °C degrees Celsius 6h chemical shift in parts per million downfield from tetramethylsilane DCM di chloromethane (CH2Q2) DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate EtOAc ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry P micro m multiplet (spectral); meter(s); milli M molar M+ parent molecular ion Me methyl MsCl methanesulfonyl chloride MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) d doublet (spectral) t triplet (spectral) m multiplet (spectral) SFC Supercritical fluid chromatography T temperature TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid THF tetrahydrofuran TPP Triphenylphosphine EDC N-(Dimethylaminopropyl)-N’-ethyl-carbodiimide HOAt 1 -Hydroxy-7-azabenzotri azole TSTU N’-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate AOP (7-Azabenzotriazol-1 -yl)oxytris(dimethylamino) phosphonium Hexafluorophosphate PyAOP hexafluorophosphate (7-Azabenzotriazol-1 -yloxy)tripyrrolidinophosphonium EEDQ 2-Ethoxy-1 -ethoxy carbonyl-1,2-dihydroquinoline Pfp Pentafluorophenyl NAC N-Acetyl Cysteine NIS N-Iodosuccinimide NMM N-Methylmorpholine Preparation of Drug Linkers Example 1: Synthesis of Drug-Linker compound 18
[00357] Compounds 6 and 14 were prepared as shown in schemes 1 and 2 and coupled to provide Drug-Linker 18 as shown in scheme 3. Scheme 1
[00358] To a solution of Fmoc-Gly6-COOH (1, synthesized on Cl-Trt resin using standard Fmoc SPPS protocol, 116 mg, 0.2 mmol) and compound 2 (HC1 salt, 40 mg, 0.2 mmol) in anhydrous DMSO (4 mL) was added HO At (28 mg, 0.2 mmol) and EDC.HC1 (115 mg, 0.6 mmol), followed by DIEA (0.07 mL). The mixture was stirred at room temperature for 4 h. Water (30 mL) was added, and the precipitate was collected by filtration. The white solid obtained was washed with water (10 mL x 2) and dried in vacuo to give the crude Fmoc-Gly7-OBn, which was dissolved in DMF (4 mL). Piperidine (0.2 mL) was added, and the reaction was stirred at room temperature for 2 h. The mixture was poured into ether (100 mL) under stirring. The solid precipitated was collected, washed with ether (2x10 mL), and dried in vacuo to give the crude compound 3 as a white solid, which was used in the next step with no further purification.
[00359] Fmoc-Glu(tBu)-Gly3-COOH (4, synthesized on Cl-Trt resin using standard Fmoc SPPS protocol, 32 mg) and compound 3 (25 mg) were dissolved in anhydrous DMSO (3 mL). HOAt (8 mg) and EDC.HC1 (33 mg) were added, and the reaction was stirred at room temperature. After 2h, the mixture was purified directly by RP-HPLC to give compound 5 as a white solid (19 mg).
[00360] The compound 5 (19 mg) was treated with TFA / DCM (2 / 3, v / v, 2 mL) at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure to give compound 6 as a white solid (18 mg). Scheme 2
[00361] To a solution of compound 7 (1.0 g, 3.62 mmol) in methanol (30 mL) was added Pd / C (10% Pd, 0.5 g). The mixture was purged with argon gas, then filled with hydrogen, and hydrogenated for a period of 1 h. The catalyst was removed by filtration, and the solvent was evaporated to give compound 8 as a clear solid (0.6 g).
[00362] To a solution of compound 8 (600 mg, 2.38 mmol) in DCM (15 mL) was added Fmoc-L-Ala-OH (740 mg, 2.38 mmol) and EEDQ (588 mg, 2.38 mmol). The mixture was stirred at RT over a period of 20 h. The solvent was evaporated under vacuum and the resulting residue was dissolved in 3 mL of DMF. Then piperidine (0.3 mL) was added, and the mixture was stirred for 20 min. Then the mixture was purified by RP-HPLC to give compound 9 as a TFA salt (470 mg).
[00363] To a solution of compound 9 (TFA salt, 237 mg, 0.54 mmol) in anhydrous DMF (2 mL) was added Fmoc-L-Val-OH (184 mg, 0.54 mmol), PyAOP (283 mg, 0.54 mmol), and DIEA (0.4 mL). The mixture was stirred at RT over a period of 20 min. Then piperidine (0.2 mL) was added, and the mixture was stirred for 10 min. Then the mixture was purified by RP-HPLC to give compound 10 as a TFA salt (230 mg).
[00364] To a solution of compound 10 (TFA salt, 230 mg, 0.43 mmol) in anhydrous DMF (2 mL) was added acetic acid (53 mg, 0.51 mol), PyAOP (224 mg, 0.43 mmol) and DIEA (0.3 mL). The mixture was stirred at room temperature for a period of 20 min. Then the mixture was purified directly by RP-HPLC to give compound 11 as a tan solid (117 mg).
[00365] To a solution of compound 11 (50 mg, 0.11 mmol) in anhydrous DMF (2 mL) was added bis(4-nitrophenyl) carbonate (66 mg, 0.22 mol) and DIEA (18 pL). The mixture was stirred at room temperature for a period of 24 h to give a solution of compound 12. Then a solution of exatecan mesylate (85 mg, 0.16 mmol) and DIEA (30 pL) in 1 mL of anhydrous DMF was added, and the stirring continued for 2 d. Then the mixture was purified by RP-HPLC to give compound 13 as a pale-yellow solid (70 mg).
[00366] Compound 13 (70 mg, 75.7 pmol) was dissolved in a mixture of DCM (3 mL) and TFA (1 mL). The mixture was stirred at room temperature for a period of 15 min, then the solvent was removed under vacuum, and the residue was purified by RP-HPLC to give compound 14 as a TFA salt (66 mg). Scheme 3
[00367] To a stirred solution of compound 6 (18 mg) and compound 14 (TFA salt, 18 mg) in anhydrous DMSO (4 mL) was added HOAt (3 mg), followed by EDC.HC1 (10 mg) and DIEA (0.01 mL). The mixture was stirred at room temperature for 1 h. Water (20 mL) was added, and the precipitated solid was collected, washed with water (5 mL) and acetonitrile (5 mL x 2). The solid obtained was suspended in DMF / DMSO (1 / 1, v / v, 4 mL). Piperidine (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. Ether (20 mL) was added, and the solid precipitated was washed with ether (10 mL x 2) and suspended in acetonitrile / water (6 / 4, v / v, 4 mL). NaOH (IN, aq., 0.4 mL) was added and the solution was stirred at room temperature. After Ih, TFA (0.3 mL) was added, followed by DMSO (3 mL). The mixture was purified directly by RP-HPLC to give compound 16 as a yellow solid after lyophilization (9 mg).
[00368] Compound 16 (9 mg) and the Pfp ester (17, 6 mg) were dissolved in DMSO (2 mL), and DIEA (0.004 mL) was added. After stirring at room temperature for 1 h. the mixture was purified by RP-HPLC to give compound 18 as a yellow solid (6 mg) after lyophilization. MS: m / z 1822.4 [M+H]+. Example 2: Synthesis of Drug-Linker compound 25
[00369] To a solution of Fmoc-Glu(tBu)-COOH.H2O (44 mg, 0.1 mmol) in DMF (2 mL) was added TSTU (32 mg), followed by DIEA (0.035 mL). The mixture was stirred at room temperature. After 10 min, beta-Alanine (10 mg) in water (0.5 mL) was added, followed by DIEA (0.02 mL). After stirring at room temperature for 30 min, the crude product was purified by RP-HPLC to give compound 20 as a white solid (48 mg), which was dissolved in DMF (2 mL). TSTU (32 mg) was added, followed by DIEA (0.04 mL). After 10 min, the sulfate (21, 28 mg) in water (0.5 mL) was added, followed by DIEA (0.06 mL). After stirring at room temperature for 1 h, the crude product was purified by RP-HPLC to give compound 22 as a white solid (TEA salt, 61 mg).
[00370] The compound 22 (61 mg) was treated with TFA / DCM (2 / 3, v / v, 3 mL) at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure to give compound 23 as a white solid which was used directly in the next step.
[00371] Compound 23 (TEA salt, 20 mg) and compound 14 (TFA salt, 19 mg) were dissolved in anhydrous DMF (2 mL). AOP (12 mg) was added, followed by DIEA (0.02 mL), and the mixture was stirred at room temperature. After 30 mins, piperidine (0.1 mL) was added, and the mixture was stirred at room temperature for 15 min. The crude product was purified by RP-HPLC to give compound 24 as a yellow solid (TFA salt, 18 mg).
[00372] Compound 24 (18 mg) and the Pfp ester (17, 9 mg) were dissolved in DMF (2 mL), and DIEA (0.01 mL) was added. After stirring at room temperature for 4 h, the mixture was purified by RP-HPLC to give compound 25 as an off-white solid (16 mg, NELT salt) after lyophilization. MS: m / z 1443.4 [M-H]'. Example 3: Synthesis of Drug-Linker compound 34
[00373] Compound 31 was prepared as shown in scheme 4 and coupled with compound 14 to provide Drug-Linker 34 as shown in scheme 5. Scheme 4
[00374] To a solution of Fmoc-Sar6-COOH (26, synthesized on Cl-Trt resin using standard Fmoc SPPS protocol, 66 mg, 0.1 mmol) and compound 27 (HC1 salt, 22 mg, 0.1 mmol) in anhydrous DMF (2 mL) was added PyAOP (52 mg, 0.1 mmol), followed by DIEA (0.07 mL). The mixture was stirred at room temperature for 10 mins. Piperidine (0.1 mL) was added, and the reaction was stirred at room temperature for 20 mins. The crude reaction mixture was purified directly by RP-HPLC to give compound 28 as a white solid (TFA salt, 66 mg).
[00375] Fmoc-Glu(tBu)-Sar3-COOH (29, synthesized on Cl-Trt resin using standard Fmoc SPPS protocol, 60 mg) and compound 28 (66 mg) were dissolved in anhydrous DMF (2 mL). AOP (44 mg) and DIEA (0.05 mL) were added, and the reaction was stirred at room temperature. After 15 mins, the mixture was purified directly by RP-HPLC to give compound 30 as a white solid (110 mg).
[00376] The compound 30 (110 mg) was treated with TFA / DCM (1 / 1, v / v, 3 mL) at room temperature for 20 mins. The mixture was concentrated to dryness under reduced pressure to give compound 31 as a white solid. Scheme 5
[00377] Compound 31 (13 mg) and compound 14 (TFA salt, 9 mg) were dissolved in anhydrous DMF (1 mL). PyAOP (7 mg) was added, followed by DIEA (0.01 mL), and the mixture was stirred at room temperature. After 1 hour, piperidine (0.05 mL) was added, and the mixture was stirred at room temperature for 10 min. The crude product was purified by RP-HPLC to give compound 32 as a yellow solid (TFA salt, 15 mg), which was dissolved in acetonitrile / water (6 / 4, v / v, 2 mL). NaOH (IN, aq., 0.1 mL) was added and the solution was stirred at room temperature. After Ih, TFA (0.1 mL) was added, and the mixture was purified directly by RP-HPLC to give compound 33 as a yellow solid after lyophilization (11 mg).
[00378] Compound 33 (10 mg) and the Pfp ester (17, 4 mg) were dissolved in DMF (1 mL), and DIEA (0.005 mL) was added. After stirring at room temperature for 2 h, the mixture was purified by RP-HPLC to give compound 34 as a yellow solid (10 mg) after lyophilization. MS: m / z 1963.0 [M+H]+. Example 4: Synthesis of Drug-Linker compound 37
[00379] Compound 35 (11 mg, purchased from InnoPep, San Diego, CA) and compound 14 (TFA salt, 9 mg) were dissolved in anhydrous DMF (1 mL). PyAOP (6 mg) was added, followed by DIEA (0.007 mL), and the mixture was stirred at room temperature. After 2 hour, piperidine (0.05 mL) was added, and the mixture was stirred at room temperature for 10 min. The crude product was purified by RP-HPLC to give compound 36 as a yellow solid (TFA salt, 13 mg).
[00380] Compound 36 (13 mg) and the Pfp ester (17, 4 mg) were dissolved in DMF (1 mL), and DIEA (0.005 mL) was added. After stirring at room temperature for 1 h, the mixture was purified by RP-HPLC to give compound 37 as a yellow solid (11 mg) after lyophilization. MS: m / z 1891.9 [M+H]+.
[00381] Compound 37-1 and compound 37-2, were prepared in a similar manner as compound 37. o
[00382] Compound 38 (14 mg, purchased from InnoPep, San Diego, CA) and compound 14 (TFA salt, 9 mg) were dissolved in anhydrous DMF (1 mL). PyAOP (6 mg) was added, followed by DIEA (0.007 mL), and the mixture was stirred at room temperature. After 2 hour, piperidine (0.05 mL) was added, and the mixture was stirred at room temperature for 10 min. The crude product was purified by RP-HPLC to give compound 39 as a yellow solid (TFA salt, 17 mg).
[00383] Compound 39 (17 mg) and the Pfp ester (17, 5 mg) were dissolved in DMF (1 mL), and DIEA (0.007 mL) was added. After stirring at room temperature for 1 h, the mixture was purified by RP-HPLC to give compound 40 as a yellow solid (17 mg) after lyophilization. MS: m / z 1071.7 [M+2H+] / 2 Example 6: Synthesis of Drug-Linker compound 43
[00384] Compound 41 (21 mg, purchased from InnoPep, San Diego, CA) and compound 14 (TFA salt, 9 mg) were dissolved in anhydrous DMF (1 mL). PyAOP (6 mg) was added, followed by DIEA (0.007 mL), and the mixture was stirred at room temperature. After 2 hour, piperidine (0.05 mL) was added, and the mixture was stirred at room temperature for 10 min. The crude product was purified by RP-HPLC to give compound 42 as a yellow solid (TFA salt, 24 mg).
[00385] Compound 42 (14 mg) and the Pfp ester (17, 3 mg) were dissolved in DMF (1 mL), and DIEA (0.005 mL) was added. After stirring at room temperature for 2 h, the mixture was purified by RP-HPLC to give compound 43 as a yellow solid (14 mg) after lyophilization. MS: m / z 1487.5 [M+2H+] / 2 Example 7: Synthesis of Drug-Linker compound 58
[00386] Compound 58 was prepared as shown in schemes 6-8. Scheme 6 AcO" AcO- ^-OAc X-O CbzHN AcO' OBn -Q SEt NPht 45 46 45 51
[00387] Compound 44 (2.9 g, 5 mmol, Eur. J. Org. Chem., 2013, 7382-7390) and compound 45 (1.2 g, 2.5 mmol, Eur. J. Org. Chem., 2006, 5158-5166) were dissolved in anhydrous toluene (30 mL) and cooled to -78 °C. BF3.Et2O (0.16 mL) was added dropwise. The reaction mixture was stirred at this temperature for 2 h, then it was warmed slowly to room temperature over a period of 3 h. Triethylamine (1 mL) was added, and the reaction was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, EtOAc / hexanes, 1 / 3 to 1 / 1) to give disaccharide 46 (1.3 g) as an amorphous white solid.
[00388] Compound 45 (2.4 g, 5 mmol) was dissolved in anhydrous DCM (50 mL). To this solution, pyridine (1.6 mL) was added, followed by FmocCl (10 mmol, 2.6 g), and the reaction was stirred at room temperature for 2 h. The mixture was diluted with DCM (50 mL) and washed with 1 N hydrochloric acid (40 mL) and water (50 mL). The organic layer was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc / hexanes, 1 / 10 to 1 / 3) to give compound 47 (2.9 g) as an amorphous white solid.
[00389] A solution of compound 47 (2.3 g) and compound 48 (1 g) in anhydrous DCM (30 mL) was stirred at room temperature in the presence of molecular sieves 4A under argon atmosphere for 30 min. The mixture was cooled in an ice bath, and NIS (0.95 g) and TfOH (0.084 mL) were added. The reaction was stirred at this temperature, and after 30 mins, molecular sieves were removed by filtration and the filtrate was washed successively with Na2S20s (10% in water, 40 mL) and water (50 mL). The organic layer was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc / hexanes, 1 / 3 to 1 / 1) to give compound 49 (1.8 g) as an amorphous white solid.
[00390] Compound 49 (1.8 g) was dissolved in DCM (20 mL). To this solution, TEA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the crude product was purified by column chromatography (silica gel, EtOAc / hexanes, 1 / 2 to 2 / 1) to give compound 50 (1.3 g) as an amorphous white solid.
[00391] A solution of compound 46 (0.33 g) and compound 50 (0.27 g) in anhydrous DCM (6 mL) was stirred at room temperature in the presence of molecular sieves 4A under argon atmosphere for 30 min. The mixture was cooled in an ice bath, and NIS (0.1 g) and TfOH (0.006 mL) were added. The reaction was stirred at this temperature, and after 30 mins, the reaction was diluted with DCM (30 mL) and molecular sieves were removed by filtration and the filtrate was washed successively with Na2S2O3 (10% in water, 20 mL) and water (20 mL). The organic layer was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc / hexanes, 1 / 3 to 2 / 1) to give compound 51 (0.35 g) as an amorphous white solid. Scheme 7 OAc ^-OBn 0Bn QBn ----► ^00^-4^ o-hn 51 ^OH ^OBn oBn ^OBn • ,NH HO AcHN H °4cHN HONHAc Cbz 53 OH ^OH QH OH NH2H0 AcHN H° AcHiM H0 NHAc 54 Fmocx / NH __.OH r-°H OH yN ° FmoCx ^0-^^^073^^40 4° 0 20 / -4NH H0 AcHN h’ '__________0^7 VN ° xtj 0 55 r-OBn .QBn ^-OBn '° NHAcC°^fjp4C° NHAc 52 5Toh r-OH o
[00392] Tetrasaccharide 51 (60 mg) and ethylenediamine (0.4 mL) were suspended in anhydrous EtOH (6 mL) and the mixture was stirred at 60 °C for 18 h. The volatiles were then evaporated under reduced pressure, and the residue was dissolved in pyridine (3 mL). Acetic anhydride (2 mL) was added, and the mixture was stirred at room temperature for 18 h. MeOH (3 mL) was added, and the volatiles were removed under reduced pressure. The residue was purified directly by RP-HPLC to give compound 52 as a white solid (41 mg).
[00393] Compound 52 (40 mg) was dissolved in MeOH (10 mL). MeONa (4.4 M in MeOH, 0.16 mL) was added, and the mixture was stirred at room temperature. After 18 h, HC1 (4M in dioxane, 0.2 mL) was added to neutralize the reaction. The reaction mixture was evaporated to dryness under reduced pressure. The residue was suspended in EtOH / water (1 / 1, v / v, 10 mL). Pd / C (40 mg) was added, and the mixture was stirred under hydrogen atmosphere for 3 h. The reaction was then filtered, and the filtrate was concentrated to dryness under reduced pressure to give compound 54 (20 mg) which was used in the next step without further purification.
[00394] To a suspension of compound 54 (20 mg) and compound 20 (27 mg) in DMF (4 mL) was added AOP (24 mg), followed by NMM (0.012 mL). The mixture was stirred at room temperature for 3 h, and the crude product was purified by RP-HPLC to give compound 55 as a white solid (21 mg), which was treated with TFA / DCM (1 / 2, v / v, 2 mL) for 1 h. The reaction was then concentrated to dryness under reduced pressure to give compound 56 (18 mg) as an amorphous solid. Scheme 8
[00395] Compound 56 (18 mg) and compound 14 (TFA salt, 17 mg) were dissolved in anhydrous DMF (2 mL). PyAOP (15 mg) was added, followed by DIEA (0.011 mL), and the mixture was stirred at room temperature. After 5 hour, piperidine (0.1 mL) was added, and the mixture was stirred at room temperature for 30 min. The crude product was purified by RP-HPLC to give compound 57 as a yellow solid (TFA salt, 14 mg).
[00396] Compound 57 (14 mg) and the Pfp ester (17, 6 mg) were dissolved in DMF (2 mL), and DIEA (0.006 mL) was added. After stirring at room temperature for 5 h, the mixture was purified by RP-HPLC to give compound 58 as a yellow solid (8 mg) after lyophilization. MS: m / z 1054.4 [M+2H+] / 2. Example 8: Synthesis of Drug-Linker compound 78
[00397] Compounds 69 was prepared as shown in scheme 9 and coupled with exatecan to provide Drug-Linker 78 as shown in scheme 10. Scheme 9 OH 67
[00398] To a solution of compound 58 (807 mg, 3.51 mmol) in anhydrous DCM (3 mL) and pyridine (4 mL) was added Fmoc-L-Ala-Cl (1.43 g, 4.4 mmol) in 3 mL of DCM. The mixture was stirred at room temperature over a period of 30 min. Then ether (10 mL) was added, and the precipitate was filtered, washed with 10 mL of water and dried. This precipitate was dissolved in anhydrous DMF (6 mL) and piperidine (1 mL) was added. The mixture was stirred for 20 min, then it was purified by RP-HPLC to give compound 59 as a tan solid (630 mg).
[00399] To a solution of compound 59 (TFA salt, 630 mg, 1.52 mmol) in anhydrous DMF (4 mL) was added Fmoc-L-Val-OH (518 mg, 1.52 mmol), PyAOP (797 mg, 1.52 mmol), and DIEA (1 mL). The mixture was stirred at room temperature over a period of 20 min. Then piperidine (0.6 mL) was added, and the stirring continued for another 20 min. Then the mixture was purified by RP-HPLC to give compound 60 as a tan solid (730 mg).
[00400] To a solution of compound 60 (TFA salt, 730 mg, 1.42 mmol) in anhydrous DMF (3 mL) was added DIEA (1 mL), and acetic anhydride (290 mg, 2.84 mmol). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 61 as a white solid (353 mg).
[00401] To a solution of compound 61 (350 mg, 0.79 mmol) in a mixture of DMF (2 mL) and water (1 mL) was added IN NaOH (2 mL). The mixture was stirred at room temperature over a period of 2 h. Then the mixture was purified by RP-HPLC to give compound 62 as a white solid (253 mg).
[00402] To a solution of compound 62 (184 mg, 0.43 mmol) in a mixture of DME (10 mL) and water (10 mL) was added sodium bicarbonate (144 mg, 1.72 mmol), pinacol vinylboronate (132 mg, 0.86 mmol) and Pd(PPh3)4 (25 mg, 0.02 mmol). The mixture was stirred at 80 °C over a period of 20 h. Then the mixture was cooled to room temperature and purified by RP-HPLC to give compound 63 as a white solid (145 mg).
[00403] To a solution of compound 63 (145 mg, 0.39 mmol) in a mixture of acetone (5 mL) and water (3 mL) was added NMO (68 mg, 0.58 mmol), and osmium tetroxide (4% in water, 25 pL, 0.01 eq). The mixture was stirred at room temperature over a period of 3 h. Then the mixture was purified by RP-HPLC to give compound 64 as a white solid (100 mg).
[00404] To a solution of compound 64 (100 mg, 0.24 mmol) in DCM (4 mL) was added trimethyl silyldiazomethane (0.6 M in hexane, 0.41 mL, 0.24 mmol). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 65 as a white solid (80 mg).
[00405] To a solution of compound 65 (80 mg, 0.188 mmol) in pyridine (2 mL) was added p-toluenesulfonyl chloride (72 mg, 0.376 mmol). The mixture was stirred at room temperature over a period of 2 h. Then the mixture was purified by RP-HPLC to give compound 66 as a tan solid (77 mg).
[00406] To a solution of compound 66 (77 mg, 0.133 mmol) in DMF (2 mL) was added sodium azide (86 mg, 1.33 mmol). The mixture was stirred at 80 °C over a period of 2 h. Then the mixture was cooled to room temperature and purified by RP-HPLC to give compound 67 as a white solid (50 mg).
[00407] To a solution of compound 67 (36 mg, 80 pmol) in THF (5 mL) was added PPh3 (31 mg, 120 pmol). The mixture was stirred at room temperature over a period of 20 h. Then the mixture was purified by RP-HPLC to give compound 68 as a white solid (30 mg).
[00408] To a solution of compound 68 (TFA salt, 17 mg, 32 pmol) in DMF (2 mL) was added di-tert-butyl dicarbonate (14 mg, 63 pmol), and DIEA (11 pL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 69 as a white solid (15 mg).
[00409] To a solution of compound 69 (15 mg, 28 pmol) in anhydrous DMF (1 mL) was added bis (4-nitrophenyl) carbonate (8.6 mg, 28 pmol) and DIEA (5.0 pL). The mixture was stirred at room temperature over 2 d. Then exatecan mesylate (15 mg, 28 pmol) and DIEA (10 pL) was added to the reaction. The mixture was stirred at 60 °C over a period of 5 h. Then the mixture was cooled to room temperature and purified by RP-HPLC to give compound 70 as a yellow solid (24 mg).
[00410] To a solution of compound 70 (24 mg, 24 pmol) in a mixture of ACN (2 mL) and water (1 mL) was added IN NaOH in water (1 mL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 71 as a yellow solid (14 mg).
[00411] To a solution of compound 71 (10 mg, 11 pmol) in anhydrous DMF (1 mL) was added compound 72 (HC1 salt, 4.6 mg, 22 mmol), PyAOP (11 mg, 20 pmol), and DIEA (18 pL). The mixture was stirred at 60 °C over a period of 5 h. Then the mixture was cooled to room temperature and purified by RP-HPLC to give compound 73 as a yellow solid (4 mg).
[00412] To a solution of compound 73 (4 mg, 3.5 pmol) in a mixture of ACN (0.6 mL) and water (0.4 mL) was added IN NaOH in water (0.1 mL). The mixture was stirred at room temperature over a period of 20 min. Then IN HC1 (0.1 mL) was added, and the mixture was evaporated to dryness under vacuum. The remaining residue was dissolved in anhydrous DMF (1 mL) and compound 74 (3.0 mg, 3.5 pmol), PyAOP (1.8 mg, 3.5 pmol), and DIEA (3 pL) was added. The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 75 as a yellow solid (5 mg).
[00413] To a solution of compound 75 (5 mg, 2.8 pmol) in a mixture of ACN (0.6 mL) and water (0.4 mL) was added IN NaOH in water (0.1 mL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 76 as a yellow solid (3.3 mg).
[00414] To a solution of compound 76 (3.3 mg, 2.0 pmol) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was evaporated to dryness under vacuum. The remaining residue was dissolved in anhydrous DMF (1 mL) and compound 77 (1.0 mg, 2.0 pmol), and DIEA (3 pL) was added. The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 78 as a yellowish solid (3.0 mg). MS: m / z 1878.5 [M+H]+. Example 9: Synthesis of Drug-Linker compound 95
[00415] Compounds 88 was prepared as shown in scheme 11 and coupled with exatecan to provide Drug-Linker 95 as shown in scheme 12. Scheme 11 79 81 0H 85 OH 88
[00416] To a solution of compound 79 (3.9 g, 19 mmol) in a mixture of DME (80 mL) and water (40 mL) was added sodium bicarbonate (6.4 g, 76 mmol), pinacol vinylboronate (5.92 g, 38 mmol) and Pd(PPh3)4 (1.1 g, 0.95 mmol). The mixture was stirred at 80 °C over a period of 20 h. Then the mixture was cooled to room temperature, extracted with EtOAc (150 mL), evaporated, and purified by silica gel column (Hexane / EtOAc 10%) to give compound 80 as a brown solid (2.4 g).
[00417] To a solution of AD-mix beta (22.5 g) in a mixture of tBuOH (80 mL) and water (80 mL) was added compound 80 (2.4 g, 16 mmol). The mixture was stirred at room temperature over a period of 20 h. Then the mixture was extracted with EtOAc (200 mL), evaporated, and purified by silicagel column (Hexane / EtOAc 40%) to give compound 81 as a brown solid (2.1 g)-
[00418] To a solution of compound 81 (735 mg, 4.0 mmol) in pyridine (10 mL) was added p-toluenesulfonyl chloride (759 mg, 4.0 mmol). The mixture was stirred at room temperature over a period of 3 h. Then the mixture was purified by RP-HPLC to give compound 82 as a tan solid (890 mg).
[00419] To a solution of compound 82 (759 mg, 2.2 mmol) in DMF (7 mL) was added sodium azide (876 mg, 13 mmol). The mixture was stirred at 80 °C over a period of 5 h. Then the mixture was cooled to room temperature and purified by RP-HPLC to give compound 83 as a tan solid (114 mg).
[00420] To a solution of compound 83 (88 mg, 0.42 mmol) in THF (5 mL) was added PPh3 (131 mg, 0.50 mmol). The mixture was stirred at room temperature over a period of 20 h. Then the mixture was purified by RP-HPLC to give compound 84 as a TFA salt (114 mg).
[00421] To a solution of compound 84 (TFA salt, 114 mg, 0.38 mmol) in DMF (2 mL) was added di-tert-butyl dicarbonate (84 mg, 0.38 mol), and DIEA (134 pL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 85 as a tan solid (100 mg).
[00422] To a solution of compound 85 (89 mg, 0.31 mmol) in methanol (1 mL) and water (0.5 mL) was added formic acid (0.1 mL), and Zn metal powder (0.3 g). The mixture was stirred at room temperature over a period of 20 min. Then saturated NaHCOs (10 mL) was added, and the mixture was extracted with EtOAc (90 mL) and evaporated to give crude compound 86 as a clear solid (50 mg).
[00423] To a solution of compound 86 (50 mg, 0.20 mmol) in anhydrous DCM (5 mL) was added compound 87 (46 mg, 0.20 mmol), and EEDQ (49 mg, 0.20 mmol). The mixture was stirred at room temperature over a period of 20 h. Then the solvent was evaporated under vacuum and the mixture was purified by RP-HPLC to give compound 88 as a tan solid (35 mg). Scheme 12 / '-..^NHFmoc Cr Y । O । O । O । O । O ^YN^N^fN^N^[fN^N^N^N^fN^^OBn O 1 O 1 O 1 O 1 O 91 o n^'Ynh2 H 1 / o' o l H h rVi H o 0^0 N । 0 । 0 । 0 । 0 । 0 0 1 0 1 0 1 0 1 0 92 H O i H Yn' / n-\n o A H o 0 nK / Vnh2 H Y / OyO >NH HO i 0N|0 । 0 I® | 0 । 0 ^N^N'^N'^N'^N‘^N^N'^N'^N''A3H 0 1 0 1 0 1 0 1 0 93
[00424] To a solution of compound 88 (15.8 mg, 34 pmol) in anhydrous DCM (1 mL) was added carbonyl diimidazole (11 mg, 68 pmol). The mixture was stirred at room temperature over 2 h. Then the mixture was evaporated under vacuum and a solution of exatecan mesylate (54 mg, 102 pmol) and DIEA (40 pL) in anhydrous DMF (2 mL) was added to the reaction. The mixture was stirred at 100 °C over a period of 1 h. Then the mixture was cooled to room temperature and purified by RP-HPLC to give compound 89 as a yellow solid (16 mg).
[00425] To a solution of compound 89 (16 mg, 17.3 pmol) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was evaporated to dryness under vacuum to give compound 90 as a TFA salt (16 mg).
[00426] To a solution of compound 90 (TFA salt, 16 mg, 17.0 pmol) in anhydrous DMF (2 mL) was added compound 91 (20 mg, 17.0 pmol), PyAOP (8.9 mg, 17.0 mmol), and DIE A (4 pL). The mixture was stirred at room temperature over a period of 20 min. Then piperidine (0.2 mL) was added and the stirring continued for another 20 min. Then the mixture was purified by RP-HPLC to give compound 92 as a yellow solid (21 mg).
[00427] To a solution of compound 92 (21 mg, 11.2 pmol) in a mixture of ACN (1 mL) and water (1 mL) was added IN NaOH in water (0.2 mL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 93 as a yellow solid (12.3 mg).
[00428] To a solution of compound 93 (TFA salt, 5.2 mg, 2.9 pmol) in anhydrous DMF (1 mL) was added compound 94 (1.4 mg, 2.9 pmol), and DIEA (3 pL). The mixture was stirred at room temperature over a period of 20 min. Then the mixture was purified by RP-HPLC to give compound 95 as a yellowish solid (3.0 mg). MS: m / z 1963.5 [M+H]+. Example 10: Synthesis of Drug-Linker Compound 107-S Scheme 13
[00429] Reagents and conditions: i. BOC2O, DIEA, DCM; ii. Pd / C, H2, MeOH, rt, 1 h; iii. Fmoc-Ala-OH, EEDQ, DCM, rt, 20 h. then piperi dine / DMF; iv. Fmoc-Val-OH, PyAOP, DIEA, DMF, rt., 20 min, then piperidine, rt., 10 min.; v. HOAc, PyAOP, DIEA, DMF; vi. BisPNP carbonate, DIEA, DMF, rt., 24 h; vii. exatecan mesylate, DIEA, DMF, rt., 48 h; viii. TFA / DCM, 1 / 3, rt., 15 min; ix. EDC / HOAt, DIEA, DMSO, rt., 1 h, then piperidine, rt., 2 h; x. DIEA, DMSO. Step i: tert-butyl (S)-(2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate (Compound 97)
[00430] To a solution of (S)-2-amino-l-(4-nitrophenyl)ethan-l-ol (Compound 96) (318 mg, 1.75 mmol) in anhydrous DMF (3 mL) was added DIEA (0.3 mL, 1.75 mmol), and tertbutoxycarbonyl anhydride (381 mg, 1.75 mmol). The mixture was stirred at RT for a period of 1 h. The solvent was evaporated under vacuum and the residue was purified by silica gel column (DCM 99% / MeOH 1%) to give Compound 97 as a tan solid (466 mg, 94%). Step ii: tert-butyl (S)-(2-(4-aminophenyl)-2-hydroxyethyl)carbamate (Compound 98)
[00431] To a solution of Compound 97 (238 mg, 0.84 mmol) in methanol (6 mL) was added Pd / C (10% Pd, 50 mg). The mixture was purged with argon gas, then filled with hydrogen, and hydrogenated for a period of 1 h. The catalyst was removed by filtration, and the solvent was evaporated to give Compound 98 as a clear solid (197 mg, 92%). Step iii: tert-butyl ((S)-2-(4-((S)-2-aminopropanamido)phenyl)-2-hydroxyethyl)carbamate (Compound 99)
[00432] To a solution of Compound 98 (197 mg, 0.78 mmol) in DCM (5 mL) / MeOH (1 mL) mixture was added Fmoc-L-Ala-OH (243 mg, 0.78 mmol) and EEDQ (232 mg, 0.94 mmol). The mixture was stirred at RT over a period of 20 h. The solvent was evaporated under vacuum and the resulting residue was dissolved in 2 mL of DMF. Then piperidine (0.3 mL) was added, and the mixture was stirred for 10 min. Then the mixture was purified by RP-HPLC to give Compound 99 as a TFA salt (258 mg, 76%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile Gradient: 2-30% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. Step iv: tert-butyl ((S)-2-(4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)phenyl)-2-hydroxyethyl)carbamate (Compound 100)
[00433] To a solution of Compound 99 (TFA salt, 237 mg, 0.54 mmol) in anhydrous DMF (2 mL) was added Fmoc-L-Val-OH (184 mg, 0.54 mmol), PyAOP (283 mg, 0.54 mmol), and DIEA (0.4 mL). The mixture was stirred at RT over a period of 20 min. Then piperidine (0.2 mL) was added, and the mixture was stirred for 10 min. Then the mixture was purified by RP-HPLC to give compound 100 as a TFA salt (230 mg, 79%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 2-35% B over 20 min, flow 50 mL / min. The desired compound eluted at 20 min. Step v: tert-butyl ((S)-2-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl) -2-hydroxyethyl)carbamate (Compound 101)
[00434] To a solution of Compound 100 (TFA salt, 230 mg, 0.43 mmol) in anhydrous DMF (2 mL) was added acetic acid (32 mg, 0.53 mol), PyAOP (224 mg, 0.43 mmol) and DIEA (0.3 mL). The mixture was stirred at room temperature for a period of 20 min. Then the mixture was purified directly by RP-HPLC to give Compound 101 as a tan solid (167 mg, 85%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 5-60% B over 20 min, flow 50 mL / min. The desired compound eluted at 18 min. Step vi and Step vii: (S)-l-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido) phenyl)-2-((tert-butoxycarbonyl)amino)ethyl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4- methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 103)
[00435] To a solution of Compound 101 (104 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added bis(4-nitrophenyl) carbonate (77 mg, 0.25 mol) and DIEA (38 pL). The mixture was stirred at room temperature for a period of 24 h to give a solution of tert-butyl ((S)-2-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl)-2-(((4-nitrophenoxy)carbonyl)oxy)ethyl)carbamate (compound 102). Then a solution of exatecan mesylate (133 mg, 0.25 mmol) and DIEA (80 pL) in 1 mL of anhydrous DMF was added, and the stirring continued for 2 d. Then the mixture was purified by RP-HPLC to give Compound 103 as a pale-yellow solid (111 mg, 60%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 15-75% B over 20 min, flow 50 mL / min. The desired compound eluted at 20 min. Step viii: (S)-l-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl)-2-aminoethyl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 104)
[00436] Compound 103 (70 mg, 75.7 pmol) was dissolved in a mixture of DCM (3 mL) and TFA (1 mL). The mixture was stirred at room temperature for a period of 15 min, then the solvent was removed under vacuum, and the residue was purified by RP-HPLC to give Compound 104 as a TFA salt (58 mg, 81%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 5-50% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. Step ix: (32S,38S)-38-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl)-l,32-diamino-3,9,15,21,27-pentamethyl-l,4,7,10,13,16,19,22,25,28,31,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,36-undecaazaoctatriacontan-38-yl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 106)
[00437] To a solution of Compound 104 (TFA salt, 30 mg, 32 pmol) in anhydrous DMF (2 mL) was added (S)-32-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-l-amino-3,9,15,21,27-pentamethyl-l,4,7,10,13,16,19,22,25,28,31-undecaoxo-3,6,9,12,15,18,21,24,27,30-decaazapentatriacontan-3 5-oic acid (Compound 105) (32 mg, 32 pmol), PyAOP (17 mg, 32 pmol) and DIEA (23 pL). The mixture was stirred at room temperature for a period of 90 min. Then piperidine (150 pL) was added and the stirring continued for an additional 10 min. Then the mixture was purified directly by RP-HPLC to give Compound 106 as a TFA salt (34 mg, 62%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, C18, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 2-45% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. Step x: (32S,38S)-38-(4-((S)-2-((S)-2-acetamido-3- methylbutanamido)propanamido)phenyl)-l-amino-32-(2-(2-(2-(3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanamido)ethoxy) ethoxy)acetamido)-3,9,15,21,27-pentamethyl- 1,4,7,10,13,16,19,22,25,28,31,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,36- undecaazaoctatriacontan-38-yl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 107-S)
[00438] To a solution of Compound 106 (TFA salt, 34 mg, 20 pmol) in anhydrous DMF (1 mL) was added perfluorophenyl 2-(2-(2-(3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanamido) ethoxy)ethoxy)acetate (Compound 12) (10 mg, 20 pmol) and DIEA (14 pL). The mixture was stirred at room temperature for a period of 30 min. Then the mixture was purified directly by RP-HPLC to give Compound 107-S as a pale-yellow solid (26 mg, 69%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 5-50% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. MS [M+2H+] / 2 = 946.2. Example 11: Synthesis of Drug-Linker Compound 118-R Scheme 14
[00439] Reagents and conditions: i. BOC2O, DIEA, DCM; ii. Pd / C, H2, MeOH, rt, 1 h; iii. Fmoc-Ala-OH, EEDQ, DCM, rt, 20 h. then piperi dine / DMF; iv. Fmoc-Val-OH, PyAOP, DIEA, DMF, rt., 20 min, then piperidine, rt., 10 min.; v. HOAc, PyAOP, DIEA, DMF; vi. BisPNP carbonate, DIEA, DMF, rt., 24 h; vii. exatecan mesylate, DIEA, DMF, rt., 48 h; viii. TFA / DCM, 1 / 3, rt., 15 min; ix. EDC / HOAt, DIEA, DMSO, rt., 1 h, then piperidine, rt., 2 h; x. DIEA, DMSO. Step i: tert-butyl (R)-(2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate (Compound 109)
[00440] To a solution of (R)-2-amino-l-(4-nitrophenyl)ethan-l-ol (Compound 108) (318 mg, 1.75 mmol) in anhydrous DMF (3 mL) was added DIEA (0.3 mL, 1.75 mmol), and tertbutoxycarbonyl anhydride (381 mg, 1.75 mmol). The mixture was stirred at RT for a period of 1 h. The solvent was evaporated under vacuum and the residue was purified by silicagel column (DCM 99% / MeOH 1%) to give Compound 109 as a tan solid (466 mg, 94%). Step ii: tert-butyl (R)-(2-(4-aminophenyl)-2-hydroxyethyl)carbamate (Compound 110)
[00441] To a solution of Compound 109 (238 mg, 0.84 mmol) in methanol (6 mL) was added Pd / C (10% Pd, 50 mg). The mixture was purged with argon gas, then filled with hydrogen, and hydrogenated for a period of 1 h. The catalyst was removed by filtration, and the solvent was evaporated to give Compound 110 as a clear solid (197 mg, 92%). Step iii: tert-butyl ((R)-2-(4-((S)-2-aminopropanamido)phenyl)-2-hydroxyethyl)carbamate (Compound 111)
[00442] To a solution of Compound 110 (197 mg, 0.78 mmol) in DCM (5 mL) / MeOH (1 mL) mixture was added Fmoc-L-Ala-OH (243 mg, 0.78 mmol) and EEDQ (232 mg, 0.94 mmol). The mixture was stirred at RT over a period of 20 h. The solvent was evaporated under vacuum and the resulting residue was dissolved in 2 mL of DMF. Then piperidine (0.3 mL) was added, and the mixture was stirred for 10 min. Then the mixture was purified by RP-HPLC to give Compound 111 as a TFA salt (258 mg, 76%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 2-30% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. Step iv: tert-butyl ((R)-2-(4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)phenyl)-2-hydroxyethyl)carbamate (Compound 112)
[00443] To a solution of Compound 111 (TFA salt, 237 mg, 0.54 mmol) in anhydrous DMF (2 mL) was added Fmoc-L-Val-OH (184 mg, 0.54 mmol), PyAOP (283 mg, 0.54 mmol), and DIEA (0.4 mL). The mixture was stirred at RT over a period of 20 min. Then piperidine (0.2 mL) was added, and the mixture was stirred for 10 min. Then the mixture was purified by RP-HPLC to give Compound 112 as a TFA salt (230 mg, 79%).Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 2-35% B over 20 min, flow 50 mL / min. The desired compound eluted at 20 min. Step v: tert-butyl ((R)-2-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido) phenyl)-2-hydroxyethyl)carbamate (Compound 113)
[00444] To a solution of Compound 112 (TFA salt, 230 mg, 0.43 mmol) in anhydrous DMF (2 mL) was added acetic acid (32 mg, 0.53 mol), PyAOP (224 mg, 0.43 mmol) and DIEA (0.3 mL). The mixture was stirred at room temperature for a period of 20 min. Then the mixture was purified directly by RP-HPLC to give Compound 113 as a tan solid (167 mg, 85%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 5-60% B over 20 min, flow 50 mL / min. The desired compound eluted at 18 min. Step vi and Step vii: (R)-l-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido) phenyl)-2-((tert-butoxycarbonyl)amino)ethyl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 115)
[00445] To a solution of Compound 113 (104 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added bis(4-nitrophenyl) carbonate (77 mg, 0.25 mol) and DIEA (38 pL). The mixture was stirred at room temperature for a period of 24 h to give a solution of tert-butyl ((R)-2-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl)-2-(((4-nitrophenoxy)carbonyl)oxy)ethyl) carbamate (Compound 114). Then a solution of exatecan mesylate (133 mg, 0.25 mmol) and DIEA (80 pL) in 1 mL of anhydrous DMF was added, and the stirring continued for 2 d. Then the mixture was purified by RP-HPLC to give Compound 115 as a pale-yellow solid (111 mg, 60%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 15-75% B over 20 min, flow 50 mL / min. The desired compound eluted at 20 min. Step viii: (R)-l-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl)-2-aminoethyl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 116)
[00446] Compound 115 (70 mg, 75.7 pmol) was dissolved in a mixture of DCM (3 mL) and TFA (1 mL). The mixture was stirred at room temperature for a period of 15 min, then the solvent was removed under vacuum, and the residue was purified by RP-HPLC to give Compound 116 as a TFA salt (58 mg, 81%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 5-50% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. Step ix: (32S,38R)-38-(4-((S)-2-((S)-2-acetamido-3-methylbutanamido)propanamido)phenyl)-l,32-diamino-3,9,15,21,27-pentamethyl-l,4,7,10,13,16,19,22,25,28,31,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,36-undecaazaoctatriacontan-38-yl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 117)
[00447] To a solution of Compound 116 (TFA salt, 30 mg, 32 pmol) in anhydrous DMF (2 mL) was added Compound 105 (32 mg, 32 pmol), PyAOP (17 mg, 32 pmol) and DIEA (23 pL). The mixture was stirred at room temperature for a period of 90 min. Then piperidine (150 pL) was added and the stirring continued for an additional 10 min. Then the mixture was purified directly by RP-HPLC to give Compound 117 as a TFA salt (34 mg, 62%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, C18, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 245% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. Step x: (32S,38R)-38-(4-((S)-2-((S)-2-acetamido-3- methylbutanamido)propanamido)phenyl)-l-amino-32-(2-(2-(2-(3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanamido)ethoxy) ethoxy)acetamido)-3,9,15,21,27-pentamethyl-l,4,7,10,13,16,19,22,25,28,31,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,36-undecaazaoctatriacontan-38-yl ((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate (Compound 118-R)
[00448] To a solution of Compound 117 (TFA salt, 34 mg, 20 pmol) in anhydrous DMF (1 mL) was added Compound 94 (10 mg, 20 pmol) and DIEA (14 pL). The mixture was stirred at room temperature for a period of 30 min. Then the mixture was purified directly by RP-HPLC to give Compound 118-R as a pale-yellow solid (26 mg, 69%). Preparative HPLC method details: Column: Phenomenex Gemini NX 5, Cl8, 110 A, 150 x 50 mm. Instrument: Shimadzu LC with CTC IFC. Mobile phase: A) water (0.1% TFA), B) acetonitrile. Gradient: 5-50% B over 20 min, flow 50 mL / min. The desired compound eluted at 17 min. MS [M+2H+] / 2 = 946.3 Example 12: Preparation of Antibody-Drug-Conjugates
[00449] The conjugates were prepared using ...
Claims
1. A conjugate of the Formula (XX):L'M21S2S2I R4°^S1. dY (K1)m0^ / 0Formula (XX)or a pharmaceutically acceptable salt thereof, wherein;L is a Targeting Unit, wherein the Targeting Unit is an anti-PTK7 antibody or an antigenbinding portion thereof;(K2-(S4)p)nXR40 is independently selected from hydrogen, Y, and ' ;D is selected from a Drug unit;n is selected from 0 and 1;m is selected from 0 and 1;wherein at least n or m is 1;p is selected from 0 and 1;z is selected from 0 and 1;X is selected from CH and N;Y is a -O-T1 and -NH-T2;T1 is a sugar cleavable unit;T2 is peptide cleavable unit;S1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)--S(0)2- or -P(O)(R20)2-; (iii) one or more amino acid(s); (iv) one or more N-substituted aminoacid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;S2 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(0)2- - S(O)2N(R20)- -0-, -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -0(0)-, -00(0)-, -0(0)0-, -S-, -S(0)--S(0)2- or -P(O)(R20)2-; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;S3 is selected from a spacer, wherein the spacer is preferably phenylene, wherein S3 is present or absent;S4 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-;wherein the optional substituents on M2, K1, K2, S1, S2, S3, and S4 are independently selected at each occurrence from:(i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -o-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), and -CN;(ii) Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2,-N(R30)C(O)R30-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -0-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and(iii) C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, Ci-6 alkyl, C2.6 alkenyl, and C2-6 alkynyl;M2 is a connector unit;K1 is selected from:(i) a peptide unit,(ii) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the Ci-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2- - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)--S(0)2- or-P(O)(R20)2-;(iii) an oligosaccharide; and(iv) a poly ether;K2 is selected from:(i) a peptide unit,(ii) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the Ci-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -0(0)-, -00(0)-, -0(0)0-, -S-, -S(0)--S(0)2- or-P(O)(R20)2-;(iii) an oligosaccharide; and(iv) a poly ether;each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -ON, -N02, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12membered heterocycle; andeach R30 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12membered heterocycle.
2. The conjugate or salt of claim 1, wherein when X is CH, D is exatecan or MMAE, m is 1, n is 0, and K1 is a polysarcosine, the polysarcosine contains 2-9 sarcosines or 13-30 sarcosines.
3. The conjugate or salt of claims 1 or 2, wherein Formula (XX) is represented by l'm21S3S2 I ( (K1)m0^0D Formula (XXI) orFormula (XXII)or a pharmaceutically acceptable salt thereof.
4. The conjugate or salt of any one of claims 1 to 3, wherein Formula (XX) is represented byFormula (XXIII)or a pharmaceutically acceptable salt thereof.
5. The conjugate or salt of any one of claims 1 to 3, wherein Formula (XX) is representedby(K2-(S4)n)DM2 iS3S2Sk 1(K1)mFormula (A)or a pharmaceutically acceptable salt thereof.
6. The conjugate or salt of any one of claims 1 to 3, wherein Formula (A) is represented byLs M2ID Formula (A-l)or a pharmaceutically acceptable salt thereof.
7. The conjugate or salt of any one of claims 1 to 6, wherein S1 is selected from: (i) anoptionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2- - S(O)2N(R20)- -0- -C(O)-, -OC(O)-, -0(0)0-, -S-, -S(O)-, -S(0)2- or -P(O)(R20)2-.
8. The conjugate or salt of any one of claims 1 to 7, where S1 is selected from: (i) an optionally substituted Ce-Cio alkylene wherein one or more alkylene units of the Ce-Cio alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, or -0(0)-.
9. The conjugate or salt of any one of claims 1 to 8, wherein S1 is a branched alkylene.
10. The conjugate or salt of any one of claims 1 to 9, wherein S1 is represented by^NH1-4 / 1-4 O11. The conjugate or salt of any one of claims 1 to 10, wherein S1 is represented by ^NH0 012. The conjugate or salt of any one of claims 1 to 11, wherein S2 is selected from: (i) an optionally substituted Cs-Ci2 alkylene wherein one or more alkylene units of the Cs-Ci2 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -0-, and -C(0)-.
13. The conjugate or salt of any one of claims 1 to 12, wherein S2 is a linear alkylene.
14. The conjugate or salt of any one of claims 1 to 13, wherein S2 is represented by015. The conjugate or salt of any one of claims 1 to 14, wherein S2 is represented by16. The conjugate or salt of any one of claims 1 to 15, wherein M2 is selected from17. The conjugate or salt of any one of claims 1 to 16, wherein M2 is selected from18.The conjugate or salt of any one of claims 1 to 17, wherein M2 is O19.The conjugate or salt of any one of claims 1 to 17, wherein M2 is20.The conjugate or salt of any one of claims 1 to 17, wherein M2 is21. The conjugate or salt of claim 18, wherein Formula (A) is represented byK1DFormula (A-2)or a pharmaceutically acceptable salt thereof.
22. The conjugate or salt of any one of claims 1 to 21, wherein X is CH.
23. The conjugate or salt of any one of claims 1 to 21, wherein X is N.
24. The conjugate or salt of any one of claims 1 to 23, wherein S3 is present and is aphenylene.25.26.The conjugate or salt of any one of claims 1 to 23, wherein S3 is absent.The conjugate or salt of any one of claims 1 to 25, wherein Formula (A) is representedbyDARFormula (A-7)wherein DAR is a drug to antibody ratio, or a pharmaceutically acceptable salt thereof.
27. The conjugate or salt of any one of claims 1 to 26, wherein Formula (A) is represented byDARFormula (A-8), wherein DAR is a drug to antibody ratio, or a pharmaceutically acceptable salt thereof.
28. The conjugate or salt of any one of claims 1 to 27, wherein each K1 is selected from a peptide unit.
29. The conjugate or salt of any one of claims 1 to 28, wherein the peptide unit of K1 has 1 to 50 amino acids.
30. The conjugate or salt of any one of claims 1 to 29, wherein the amino acids of K1 is selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and P-Alanine.
31. The conjugate or salt of any one of claims 1 to 30, wherein the amino acids of K1 is selected from a group consisting of glycine, sarcosine, proline, serine, alanine, and P-Alanine.
32. The conjugate or salt of any one of claims 1 to 31, wherein the peptide unit of K1 has a terminus unit.
33. The conjugate or salt of any one of claims 1 to 32, wherein K1 is selected from, and, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.
34. The conjugate or salt of any one of claims 1 to 33, wherein K1 is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.
35. The conjugate or salt of any one of claims 1 to 33, wherein K1 is selected from, and, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.
36. The conjugate or salt of any one of claims 1 to 35, wherein K1 is selected from37. The conjugate or salt of any one of claims 1 to 33, 35, or 36, wherein K1 is selected from38. The conjugate or salt of any one of claims 1 to 33, or 37, wherein K1 is selected from wJ , wherein j is selected from 5 to 15.
39. The conjugate or salt of any one of claims 1 to 33, or 37, wherein K1 is selected fromJ , wherein j is selected from 3 to 8.
40. The conjugate or salt of any one of claims 1 to 33, or 37, wherein K1 is selected fromJ , wherein j is selected from 3 to 8.
41. The conjugate or salt of any one of claims 33 to 40, wherein R6 is selected from -OR7 and -NHR7, wherein R7 is selected from hydrogen; Cnio alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.
42. The conjugate or salt of any one of claims 33 to 41, wherein R6 is selected from -OH, -ANH2, and " O OH.
43. The conjugate or salt of any one of claims 33 to 41, wherein R6 is -OH.
44. The conjugate or salt of any one of claims 33 to 36, wherein R6 is -NH2.N / ? H45. The conjugate or salt of any one of claims 33 to 36, wherein R6 is H O .
46. The conjugate or salt of any one of claims 1 to 32, wherein K1 is selected from, and50.The conjugate or salt of any one of claims 1 to 32, wherein K1 isNH51. The conjugate or salt of any one of claims 1 to 32, wherein K1 is selected from52. The conjugate or salt of any one of claims 1 to 32, wherein K1 is 0 5 / (nV^nh.
53. The conjugate or salt of any one of claims 1 to 32, wherein K1 is 0 554. The conjugate or salt of any one of claims 1 to 32, wherein K1 is selected from55. The conjugate or salt of any one of claims 1 to 32, wherein K1 isOH556. The conjugate or salt of any one of claims 1 to 32, wherein K1 is 0 557. The conjugate or salt of any one of claims 1 to 32, wherein K1 is selected from58.The conjugate or salt of any one of claims 1 to 32, wherein K1 is59.The conjugate or salt of any one of claims 1 to 32, wherein K1 is60.The conjugate or salt of any one of claims 1 to 32, wherein K1 is61. The conjugate or salt of any one of claims 1 to 32, wherein K1 is62. The conjugate or salt of any one of claims 1 to 32, wherein K1 is63. The conjugate or salt of any one of claims 1 to 32, wherein K1 is64. The conjugate or salt of any one of claims 1 to 32, wherein K1 is65. The conjugate or salt of any one of claims 1 to 10, wherein S1 is represented by66. The conjugate or salt of claim 65, wherein each K1 is selected from: an oligosaccharide.
67. The conjugate or salt of claim 66, wherein each K1 is selected from:
68. The conjugate or salt of claim 1, wherein Formula (A) is represented byD Formula (A-3) or a pharmaceutically acceptable salt thereof.
69. The conjugate or salt of claim 1, wherein Formula (A) is represented byl'm20^0D Formula (A-4)or a pharmaceutically acceptable salt thereof.
70. The conjugate or salt of any one of claims 68 to 69, wherein S1 is selected from: (i) an optionally substituted C1-C2 alkylene wherein one or more alkylene units of the C1-C2 alkylene are optionally and independently replaced by -N(R20)-.
71. The conjugate or salt of any one of claims 68 to 70, wherein S1 is represented by72. The conjugate or salt of any one of claims 68 to 71, wherein S2 is selected from: (i) an optionally substituted Cs-Cn alkylene wherein one or more alkylene units of the Cs-Cn alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -0-, and -C(0)-.
73. The conjugate or salt of any one of claims 68 to 72, wherein S2 is a linear alkylene.
74. The conjugate or salt of any one of claims 68 to 73, wherein S2 is represented byO75. The conjugate or salt of any one of claims 68 to 74, wherein Sx-S2 is represented by76. The conjugate or salt of any one of claims 68 to 75, wherein S3 is present and is aphenylene.
77. The conjugate or salt of any one of claims 68 to 75, wherein S3 is absent.
78. The conjugate or salt of any one of claims 68 to 77, wherein M2 is selected from79. The conjugate or salt of any one of claims 68 to 78, wherein M2 is selected from80. The conjugate or salt of any one of claims 68 to 78, wherein M2 is selected from081. The conjugate or salt of any one of claims 68 to 78, wherein M2 is OO82.The conjugate or salt of any one of claims 68 to 78, wherein M2 is 083.The conjugate or salt of any one of claims 68 to 78, wherein M2 is84. The conjugate or salt of any one of claims 68 to 81, wherein S1 -S2-M2-L is representedbyN H, wherein S3 is absent.
85. The conjugate or salt of any one of claims 68 to 81, wherein Formula (A) is representedbyor a pharmaceutically acceptable salt thereof.
86. The conjugate or salt of any one of claims 68 to 81, wherein Formula (A) is representedbyD Formula (A-6)or a pharmaceutically acceptable salt thereof.
87. The conjugate or salt of any one of claims 68 to 86, wherein p is 1.
88. The conjugate or salt of any one of claims 68 to 87, wherein S4 is selected from: (i) anoptionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -0-, or -C(0)-.
89. The conjugate or salt of any one of claims 68 to 88, wherein S4 is selected from: (i) an optionally substituted C1-C5 alkylene wherein one or more alkylene units of the C1-C5 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -0-, or -C(0)-.
90. The conjugate or salt of any one of claims 68 to 89, wherein S4 is selected from: (i) an optionally substituted C1-C3 alkylene wherein one or more alkylene units of the C1-C5 alkylene are optionally and independently replaced by -N(H)-, -N(CH3)-, -0-, or -C(0)-.O91. The conjugate or salt of any one of claims 68 to 90, wherein S4 is selected from ,92. The conjugate or salt of any one of claims 68 to 90, wherein S4 isO93. The conjugate or salt of any one of claims 68 to 90, wherein S4 is ' ' .। ?94. The conjugate or salt of any one of claims 68 to 90, wherein S4 is ' ' .
95. The conjugate or salt of any one of claims 68 to 94, wherein each K2 is selected from a peptide unit.
96. The conjugate or salt of any one of claims 68 to 95, wherein the peptide unit of K2 has 1 to 50 amino acids.
97. The conjugate or salt of claim 96, wherein the amino acids of K2 is selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine,glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and P-Alanine.
98. The conjugate or salt of claim 89, wherein the amino acids of K2 is selected from a group consisting of glycine, sarcosine, proline, serine, alanine, and P-Alanine.
99. The conjugate or salt of any one of claims 68 to 98, wherein the peptide unit of K2 has a terminus unit.
100. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected from, and101. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected from, and, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.
102. The conjugate or salt of any one of claims 68 to 98, wherein K2 is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.
103. The conjugate or salt of any one of claims 100 to 102, wherein R6 is selected from -OR7 and -NHR7, wherein R7 is selected from hydrogen; Cnio alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.
104. The conjugate or salt of any one of claims 100 to 103, wherein R6 is selected from -OH, -lj '^OHNH2, and H O .
105. The conjugate or salt of any one of claims 100 to 104, wherein R6 is -OH.
106. The conjugate or salt of any one of claims 100 to 104, wherein R6 is -NH2.
109. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected fromOH10111. The conjugate or salt of any one of claims 68 to 99, wherein K2 is'V OLH OH112. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected from113. The conjugate or salt of any one of claims 68 to 99, wherein K2 is114. The conjugate or salt of any one of claims 68 to 99, wherein K2 is115. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected fromI116. The conjugate or salt of any one of claims 68 to 99, wherein K2 is 0 5117.The conjugate or salt of any one of claims 68 to 99, wherein K2 is118. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected from119.The conjugate or salt of any one of claims 68 to 99, wherein K2 is120.The conjugate or salt of any one of claims 68 to 99, wherein K2 is121.The conjugate or salt of any one of claims 68 to 99, wherein K2 is122. The conjugate or salt of any one of claims 68 to 99, wherein K2 is123. The conjugate or salt of any one of claims 68 to 99, wherein K2 is124. The conjugate or salt of any one of claims 68 to 99, wherein K2 is125. The conjugate or salt of any one of claims 68 to 99, wherein K2 is126. The conjugate or salt of any one of claims 68 to 99, wherein K2 is selected from: an oligosaccharide.
127. The conjugate or salt of claim 126, wherein each K2 is selected from:wherein k is selected from2 to 10.
128. The conjugate or salt of claim 127, wherein each K2 is selected from:
129. The conjugate or salt of any one of claims 1 to 128, wherein the sugar cleavable unit of T1 includes a sugar.
130. The conjugate or salt of claim 129, wherein the sugar is glucuronide.O^OHH°I °HO'yAo131. The conjugate or salt of any one of claims 1 to 130, wherein Y is OH z .
132. The conjugate or salt of any one of claims 1 to 128, wherein the peptide unit of T2includes one or more amino acids selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and P-Alanine.
133. The conjugate or salt of claim 132, wherein the peptide unit of T2 includes a dipeptide or tripeptide.
134. The conjugate or salt of claim 133, wherein the peptide unit of T2 includes a dipeptide.
135. The conjugate or salt of any one of claims 132 to 134, wherein the dipeptide is selectedfrom Val-Cit, Vai-Ala and Phe-Lys.
136. The conjugate or salt of any one of claims 132 to 135, wherein the peptide unit of T2 includes a capping moiety.0137. The conjugate or salt of claim 136, wherein the capping moiety is .
138. The conjugate or salt of any one of claims 1 to 128, or 132 to 137, wherein Y is139. The conjugate or salt of any one of claims 1 to 138, wherein D is a selected from a cytotoxic agent, an immune modulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioactive isotope and a chelating ligand.
140. The conjugate or salt of any one of claims 1 to 138, wherein D is selected from a cytotoxic agent, camptothecin derivative, and an immune modulatory agent.
141. The conjugate or salt of any one of claims 1 to 138, wherein D is a selected from a cytotoxic agent, and an immune modulatory agent.
142. The conjugate or salt of any one of claims 1 to 138, wherein D is selected from exatecan, SN-38, and monomethyl auristatin E (MMAE).
143. The conjugate or salt of any one of claims 1 to 138, wherein D is selected from exatecan and monomethyl auristatin E (MMAE).
144. The conjugate or salt of any one of claims 1 to 138, wherein D is MMAE.
145. The conjugate or salt of any one of claims 1 to 138, wherein D is exatecan.
146. The conjugate or salt of any one of claims 1 to 138, wherein D is147. The conjugate or salt of any one of claims 1 to 146, having a DAR (drug to antibody ratio) of about 1 to about 10.
148. The conjugate or salt of any one of claims 1 to 147, having a DAR of about 2 to about 8.
149. The conjugate or salt of any one of claims 1 to 148, having a DAR of about 4 to about 8.
150. The conjugate or salt of any one of claims 1 to 149, having a DAR of about 4 or about 8.
151. The conjugate or salt of any one of claims 1 to 150, having a DAR of about 4.
152. The conjugate or salt of any one of claims 1 to 150, having a DAR of about 8.
153. A conjugate represented by the Formula (Aa) or Formula (Ab):or a pharmaceutically acceptable salt thereof, wherein;L is an anti-PTK7 antibody or an antigen-binding portion thereof;D is selected from a Drug unit; n is selected from 0 and 1;m is selected from 0 and 1;wherein at least n or m is 1;p is selected from 0 and 1;X is selected from CH and N;Y is a -O-T1 and -NH-T2;T1 is a sugar cleavable unit;T2 is peptide cleavable unit;S1 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(0)2- - S(O)2N(R20)- -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, —S(0)—, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)-, —S(0)2—, or -P(O)(R20)2-; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;S2 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(0)2- - S(O)2N(R20)- -0-, -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-; (ii) optionally substituted C3-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -0(0)-, -00(0)-, -0(0)0-, -S-, -S(0)-—S(0)2—, or -P(O)(R20)2-; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;S3 is selected from a spacer, wherein the spacer is preferably phenylene, wherein S3 is present or absent;S4 is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)-, -S(0)2- 5- to 6-membered heterocyclene, or -P(O)(R20)2-;wherein the optional substituents on M2, K1, K2, S1, S2, S3, and S4, are independently selected at each occurrence from:(i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -o-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), and -CN;(ii) Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2,-N(R30)C(O)R30-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -0-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and(iii) C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30 -C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, Ci-6 alkyl, C2.6 alkenyl, and C2-6 alkynyl;M2 is a connector unit;K1 is selected from:(i) a peptide unit,(ii) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the Ci-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2- - S(O)2N(R20)- -0- -C(0)-, -0C(0)-, -0(0)0-, -S-, -S(0)--S(0)2- or-P(O)(R20)2-;(iii) an oligosaccharide; and(iv) a poly ether;K2 is selected from:(i) a peptide unit,(ii) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the Ci-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2-, - S(O)2N(R20)-, -0-, -0(0)-, -00(0)-, -0(0)0-, -S-, -S(0)--S(0)2- or-P(O)(R20)2-;(iii) an oligosaccharide; and(iv) a poly ether;each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -ON, -N02, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12membered heterocycle; andeach R30 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-i2 carbocycle, and 3- to 12membered heterocycle.
154. The conjugate or salt of claim 153, wherein when X is CH, D is exatecan or MMAE, m is 1, n is 0, and K1 is a polysarcosine, the polysarcosine contains 2-9 sarcosines or 13-30 sarcosines;155. The conjugate or salt of claim 153, wherein the conjugate is represented by, wherein L is an anti-PTK7 antibody or an antigen-binding portion thereof; and DAR is a drug to antibody ratio.
156. The conjugate or salt of claim 153, wherein the conjugate is represented by\ 0, wherein L is an anti-PTK7 antibody or an antigen-binding portion thereof; and DAR is a drug to Targeting Unit (L) ratio.
157. The conjugate or salt of any one of claims 153 to 156, having a DAR of about 1 to 10.
158. The conjugate or salt of any one of claims 153 to 156, having a DAR of about 2 to 8.
159. The conjugate or salt of any one of claims 153 to 156, having a DAR about 8.
160. The conjugate or salt of any one of claims 1 to 159, wherein the antibody or portionthereof comprises a heavy chain CDR (HCDR) 1-3 and a light chain CDR (LCDR) 1-3 comprising SEQ ID NOs:151, 157, 161, 164, 167, and 170, respectively.
161. The conjugate or salt of claim 160, wherein the antibody or portion thereof comprises a heavy chain variable domain (Vh) and a light chain variable domain (Vl) comprising SEQ ID NOs:76 and 75, respectively.
162. The conjugate or salt of claim 160, wherein the antibody or portion thereof comprises a VH comprising SEQ ID NOs:154, 155, and 161, and a VL comprising SEQ ID NOs:163, 166, and 170.
163. The conjugate or salt of claim 162, wherein the antibody or portion thereof is humanized.
164. The conjugate or salt of claim 163, wherein the Vh comprises framework regions derivedfrom a human IGHV1-46*01 germline gene.
165. The conjugate or salt of claim 164, wherein the Vh comprises one or more back mutations selected from Y91F, R71V, V78A, M48I, M69L, and V20L, wherein the numbering is according to SEQ ID NO: 172.
166. The conjugate or salt of claim 163, wherein the Vl comprises framework regions derived from a human IGKV1D-16*01 germline gene.
167. The conjugate or salt of claim 166, wherein the Vl comprises one or more back mutations selected from I21L, Y36L, A43T, S46R, G66R, T69S, and F71Y, wherein the numbering is according to SEQ ID NO: 183.
168. The conjugate or salt of claim 163, whereina) the Vh comprises any one of SEQ ID NOs: 172-182, 193, 196, and 197, or an amino acid sequence at least 95% identical thereto;b) the Vl comprises any one of SEQ ID NOs: 183-192, 194, and 195, or an amino acid sequence at least 95% identical thereto; orc) a) and b).
169. The conjugate or salt of claim 168, wherein the Vh and the Vl compriseSEQ ID NOs: 178 and 188, respectively,SEQ ID NOs: 193 and 188, respectively, orSEQ ID NOs: 173 and 188, respectively.
170. The conjugate or salt of any one of claims 160 to 169, wherein the antibody comprises a human IgGi constant region.
171. The conjugate or salt of claim 170, wherein the human IgGi constant region comprises SEQ ID NO:201, optionally without the C-terminal lysine.
172. The conjugate or salt of any one of claims 160 to 170, wherein the antibody comprises a human light chain constant region that comprises SEQ ID NO: 199.
173. The conjugate or salt of any one of claims 1 to 159, wherein the antibody or portion thereof comprising a heavy chain that comprises the amino acid sequences of SEQ ID NOs: 193and 201, optionally without the C-terminal lysine, and a light chain that comprises the amino acid sequences of SEQ ID NOs:188 and 199.
174. The conjugate or salt of any one of claims 1 to 159, wherein the antibody or portion thereof comprisesa) HCDR1-3 and LCDR1-3 comprising SEQ ID NOs:204, 209, 213, 216, 219, and 222, respectively;b) Vh and Vl comprising SEQ IDNOs: 112 and 111, respectively; orc) an HC comprising SEQ ID NOs: 112 and 201, optionally without the C-terminal lysine, and an LC comprising SEQ ID NOs: 111 and 199.
175. The conjugate or salt of any one of claims 1 to 159, wherein the antibody or portion thereof comprisesa) HCDR1-3 and LCDR1-3 comprising SEQ ID NOs:226, 231, 235, 238, 241, and 244, respectively;b) Vh and Vl comprising SEQ ID NOs: 128 and 127, respectively; orc) an HC comprising SEQ ID NOs: 128 and 201, optionally without the C-terminal lysine, and an LC comprising SEQ ID NOs: 127 and 199.
176. The conjugate or salt of any one of claims 1 to 159, wherein the antibody or portion thereof comprises a heavy chain variable domain (Vh) and a light chain variable domain (Vl), wherein the Vh and the Vl comprise:SEQ ID NOs: 148 and 147, respectively;SEQ ID NOs:24 and 23, respectively;SEQ ID NOs:36 and 35, respectively;SEQ ID NOs:4 and 3, respectively;SEQ ID NOs: 10 and 9, respectively;SEQ ID NOs: 16 and 15, respectively;SEQ ID NOs: 18 and 17, respectively;SEQ ID NOs:20 and 19, respectively;SEQ ID NOs:22 and 21, respectively;SEQ ID NOs:26 and 25, respectively;SEQ ID NOs:28 and 27, respectively;SEQ ID NOs:30 and 29, respectively;SEQ ID NOs:32 and 31, respectively;SEQ ID NOs:34 and 33, respectively;SEQ ID NOs:38 and 37, respectively;SEQ ID NOs:40 and 39, respectively;SEQ ID NOs:2 and 1, respectively;SEQ ID NOs:6 and 5, respectively;SEQ ID NOs:8 and 7, respectively;SEQ ID NOs: 12 and 11, respectively;SEQ ID NOs: 14 and 13, respectively;SEQ ID NOs:42 and 41, respectively;SEQ ID NOs:44 and 43, respectively;SEQ ID NOs:52 and 51, respectively;SEQ ID NOs:54 and 53, respectively;SEQ ID NOs:56 and 55, respectively;SEQ ID NOs:46 and 45, respectively;SEQ ID NOs:48 and 47, respectively;SEQ ID NOs:50 and 49, respectively;SEQ ID NOs:82 and 81, respectively;SEQ ID NOs:80 and 79, respectively;SEQ ID NOs:58 and 57, respectively;SEQ ID NOs:60 and 59, respectively;SEQ ID NOs:62 and 61, respectively;SEQ ID NOs:64 and 63, respectively;SEQ ID NOs:66 and 65, respectively;SEQ ID NOs:68 and 67, respectively;SEQ ID NOs:70 and 69, respectively;SEQ ID NOs:72 and 71, respectively;SEQ ID NOs:74 and 73, respectively;SEQ ID NOs:76 and 75, respectively;SEQ ID NOs:78 and 77, respectively;SEQIDNOs: 112 and 111, respectively;SEQ ID NOs: 102 and 101, respectively;SEQ ID NOs: 104 and 103, respectively;SEQ ID NOs: 106 and 105, respectively;SEQ ID NOs: 108 and 107, respectively;SEQ ID NOs: 110 and 109, respectively;SEQ ID NOs:84 and 83, respectively;SEQ ID NOs:86 and 85, respectively;SEQ ID NOs:88 and 87, respectively;SEQ ID NOs:90 and 89, respectively;SEQ ID NOs:92 and 91, respectively;SEQ ID NOs:94 and 93, respectively;SEQ ID NOs:96 and 95, respectively;SEQ ID NOs:98 and 97, respectively;SEQ ID N0s:100 and 99, respectively;SEQIDNOs:114 and 113, respectively;SEQ ID NOs: 120 and 119, respectively;SEQ ID NOs: 128 and 127, respectively;SEQ ID NOs: 130 and 129, respectively;SEQ ID NOs: 132 and 131, respectively;SEQ ID NOs: 134 and 133, respectively;SEQ ID NOs: 136 and 135, respectively;SEQ ID NOs: 138 and 137, respectively;SEQ ID NOs: 140 and 139, respectively;SEQ ID NOs: 142 and 141, respectively;SEQ ID NOs: 144 and 143, respectively;SEQ ID NOs: 146 and 145, respectively;SEQ ID NOs: 116 and 115, respectively;SEQ ID NOs: 118 and 117, respectively;SEQ ID NOs: 122 and 121, respectively;SEQ ID NOs: 124 and 123, respectively;SEQ ID NOs: 126 and 125, respectively; orSEQ ID NOs: 193 and 188, respectively.
177. The conjugate or salt of any one of claims 1 to 159, wherein the antibody or portion thereof comprises a heavy chain variable domain (Vh) and a light chain variable domain (Vl), wherein the Vh and the Vl comprise:SEQ ID NOs: 148 and 147, respectively;SEQ ID NOs: 10 and 9, respectively;SEQ ID NOs: 16 and 15, respectively;SEQ ID NOs: 18 and 17, respectively;SEQ ID NOs:20 and 19, respectively;SEQ ID NOs:26 and 25, respectively;SEQ ID NOs:30 and 29, respectively;SEQIDNOs: 112 and 111, respectively;SEQ ID NOs: 110 and 109, respectively;SEQ ID NOs:86 and 85, respectively;SEQ ID NOs: 128 and 127, respectively;SEQ ID NOs: 122 and 121, respectively; orSEQ ID NOs: 193 and 188, respectively.
178. The conjugate or salt of any one of claims 176 to 177, wherein the antibody comprises a human IgGl constant region.
179. The conjugate or salt of any one of claims 176 to 178, wherein the human IgGi constant region comprises SEQ ID NO:201, optionally without the C-terminal lysine.
180. The conjugate or salt of any one of claims 176 to 178, wherein the antibody comprises a human light chain constant region that comprises SEQ ID NO: 199.
181. The conjugate or salt of any one of claims 1 to 177, wherein the PTK7 antibody is optionally without the C-terminal lysine.
182. A pharmaceutical composition comprising a conjugate of any one of claims 1 to 181 and a pharmaceutically acceptable excipient.
183. A method of treating a subject with a disease or disorder, comprising administering to the subject in need thereof a conjugate of any one of claims 1 to 180 or a pharmaceutical composition of claim 181.
184. The method of claim 182, wherein the disease or disorder is a cancer.
185. A method of treating a subject with a cancer, comprising administering to the subject in need thereof a conjugate of any one of claims 1 to 181 or a pharmaceutical composition of claim 182.
186. A method of treating a subject with a PTK7-positive cancer, comprising administering to the subject in need thereof a conjugate of any one of claims 1 to 181 or a pharmaceutical composition of claim 182.
187. The method of any one of claims 184 to 186, wherein the cancer is selected from: melanoma, skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopiantube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cell anaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV-associated T cell leukemia / lymphoma), or mesothelioma. In certain embodiments, the cancer is selected from the group consisting of head and neck cancer, bone cancer (e.g., osteosarcoma), Ewing sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple negative breast cancer), melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and chronic myelogenous leukemia. In particular embodiments, the cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, hepatic cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft-tissue sarcoma, bladder cancer, prostate cancer, renal cancer, and melanoma.
188. The method of any one of claims 184 to 186, wherein the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer.
189. The method of any one of claims 184 to 186, wherein the cancer is cell lymphoma.
190. The method of any one of claims 184 to 186, wherein the cancer is non-small cell lungcancer.
191. The method of any one of claims 184 to 186, wherein the cancer is large-cell lung cancer.
192. The method of any one of claims 184 to 186, wherein the cancer is breast cancer.
193. The method of any one of claims 184 to 186, wherein the cancer is small-cell lung cancer.
194. Use of a conjugate, for treating a subject with a disease or disorder, comprising administering to the subject in need thereof a conjugate of any one of claims 1 to 181 or a pharmaceutical composition of claim 182.
195. The use of claim 194, wherein the disease or disorder is cancer.
196. A conjugate selected from Table A, Table A-R, Table A-S, Table B, Table B-R, and Table B-S, or a pharmaceutically acceptable salt thereof.
197. A conjugate selected from Table A or a pharmaceutically acceptable salt thereof.
198. A conjugate selected from Table A-R or a pharmaceutically acceptable salt thereof.
199. A conjugate selected from Table A-S, or a pharmaceutically acceptable salt thereof.
200. A pharmaceutical composition comprising a conjugate of any one of claims 196 to 199 and a pharmaceutically acceptable excipient.
201. A method of treating a subject with a disease or disorder, comprising administering to the subject in need thereof a conjugate of any one of claims 196 to 199 or a pharmaceutical composition of claim 200.
202. The method of claim 201, wherein the disease or disorder is a cancer.
203. The method of claim 202, wherein the cancer is selected from: melanoma, skin basal cellcancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acutemyeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cell anaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV-associated T cell leukemia / lymphoma), or mesothelioma. In certain embodiments, the cancer is selected from the group consisting of head and neck cancer, bone cancer (e.g., osteosarcoma), Ewing sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple negative breast cancer), melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and chronic myelogenous leukemia. In particular embodiments, the cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, hepatic cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft-tissue sarcoma, bladder cancer, prostate cancer, renal cancer, and melanoma.
204. A conjugate represented by, or a pharmaceutically acceptable salt thereof,wherein L is an anti-PTK7 antibody or an antigen-binding portion thereof; and DAR is a drug to antibody ratio.
205. A conjugate represented by, or a pharmaceutically acceptable salt thereof,wherein L is an anti-PTK7 antibody or anantigen-binding portion thereof; and DAR is adrug to antibody ratio.
206. A conjugate represented by, or a pharmaceutically acceptable salt thereof,wherein L is an anti-PTK7 antibody or an antigen-binding portion thereof; and DAR is a drug to Targeting Unit (L) ratio.
207. A conjugate represented by, or a pharmaceutically acceptable salt thereof,wherein L is an anti-PTK7 antibody or anantigen-binding portion thereof; and DAR is adrug to antibody ratio.
208. A conjugate represented by\ 0, or a pharmaceutically acceptable salt thereof,wherein L is an anti-PTK7 antibody or an antigen-binding portion thereof; and DAR is a drug to antibody ratio.
209. A conjugate represented by, or a pharmaceutically acceptable salt thereof,wherein L is an anti-PTK7 antibody or an antigen-binding portion thereof; and DAR is a drug to Targeting Unit (L) ratio.
210. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is selected from PTK7-1; PTK7-1EL; PTK7-2; L is PTK7-3; L is PTK7-4; PTK7-5; PTK7-6;PTK7-7; PTK7-8; PTK7-9; PTK7-9EL; PTK7-10; PTK7-11; PTK7-12; PTK7-13; and PTK7-14.
211. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-1.
212. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-1EL.
213. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-2.
214. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is LisPTK7-3.
215. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is L is PTK7-4.
216. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-5.
217. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-6.
218. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-7.
219. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-8. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-9.
220. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-9EL.
221. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-10.
222. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-11.
223. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-12.
224. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-13.
225. The conjugate or salt of any one of claims 204 to 209, wherein the anti-PTK7 antibody is PTK7-14.
226. The conjugate or salt of any one of claims 204 to 209, wherein the antibody or portion thereof comprises a heavy chain CDR (HCDR) 1-3 and a light chain CDR (LCDR) 1-3 comprising SEQ ID NOs:151, 157, 161, 164, 167, and 170, respectively.
227. The conjugate or salt of claim 226, wherein the antibody or portion thereof comprises a heavy chain variable domain (Vh) and a light chain variable domain (Vl) comprising SEQ ID NOs:76 and 75, respectively.
228. The conjugate or salt of claim 226, wherein the antibody or portion thereof comprises a VH comprising SEQ ID NOs:154, 155, and 161, and a VL comprising SEQ ID NOs:163, 166, and 170.
229. The conjugate or salt of claim 228, wherein the antibody or portion thereof is humanized.
230. The conjugate or salt of claim 229, wherein the Vh comprises framework regions derivedfrom a human IGHV1-46*01 germline gene.
231. The conjugate or salt of claim 230, wherein the Vh comprises one or more back mutations selected from Y91F, R71V, V78A, M48I, M69L, and V20L, wherein the numbering is according to SEQ ID NO: 172.
232. The conjugate or salt of claim 229, wherein the Vl comprises framework regions derived from a human IGKV1D-16*01 germline gene.
233. The conjugate or salt of claim 232, wherein the Vl comprises one or more back mutations selected from I21L, Y36L, A43T, S46R, G66R, T69S, and F71Y, wherein the numbering is according to SEQ ID NO: 183.
234. The conjugate or salt of claim 229, whereina) the Vh comprises any one of SEQ ID NOs: 172-182, 193, 196, and 197, or an amino acid sequence at least 95% identical thereto;b) the Vl comprises any one of SEQ ID NOs: 183-192, 194, and 195, or an amino acid sequence at least 95% identical thereto; orc) a) and b).
235. The conjugate or salt of claim 234, wherein the Vh and the Vl compriseSEQ ID NOs: 178 and 188, respectively,SEQ ID NOs: 193 and 188, respectively, orSEQ ID NOs: 173 and 188, respectively.
236. The conjugate or salt of any one of claims 226 to 235, wherein the antibody comprises a human IgGi constant region.
237. The conjugate or salt of claim 236, wherein the human IgGi constant region comprises SEQ ID NO:201, optionally without the C-terminal lysine.
238. The conjugate or salt of any one of claims 226 to 237, wherein the antibody comprises a human light chain constant region that comprises SEQ ID NO: 199.
239. The conjugate or salt of any one of claims 226 to 238, wherein the antibody or portion thereof comprising a heavy chain that comprises the amino acid sequences of SEQ ID NOs: 193 and 201, optionally without the C-terminal lysine, and a light chain that comprises the amino acid sequences of SEQ ID NOs: 188 and 199.
240. The conjugate or salt of any one of claims 226 to 239, wherein the antibody or portion thereof comprisesa) HCDR1-3 and LCDR1-3 comprising SEQ ID NOs:204, 209, 213, 216, 219, and 222, respectively;b) Vh and Vl comprising SEQ IDNOs: 112 and 111, respectively; orc) an HC comprising SEQ ID NOs: 112 and 201, optionally without the C-terminal lysine, and an LC comprising SEQ ID NOs: 111 and 199.
241. The conjugate or salt of any one of claims 226 to 240, wherein the antibody or portion thereof comprisesa) HCDR1-3 and LCDR1-3 comprising SEQ ID NOs:226, 231, 235, 238, 241, and 244, respectively;b) Vh and Vl comprising SEQ ID NOs: 128 and 127, respectively; orc) an HC comprising SEQ ID NOs: 128 and 201, optionally without the C-terminal lysine, and an LC comprising SEQ ID NOs: 127 and 199.
242. The conjugate or salt of any one of claims 226 to 241, wherein the antibody or portion thereof comprises a heavy chain variable domain (Vh) and a light chain variable domain (Vl), wherein the Vh and the Vl comprise:SEQ ID NOs:148 and 147, respectively;SEQ ID NOs:24 and 23, respectively;SEQ ID NOs:36 and 35, respectively;SEQ ID NOs:4 and 3, respectively;SEQ ID NOs:10 and 9, respectively;SEQ ID NOs:16 and 15, respectively;SEQ ID NOs:18 and 17, respectively;SEQ ID NOs:20 and 19, respectively;SEQ ID NOs:22 and 21, respectively;SEQ ID NOs:26 and 25, respectively;SEQ ID NOs:28 and 27, respectively;SEQ ID NOs:30 and 29, respectively;SEQ ID NOs:32 and 31, respectively;SEQ ID NOs:34 and 33, respectively;SEQ ID NOs:38 and 37, respectively;SEQ ID NOs:40 and 39, respectively;SEQ ID NOs:2 and 1, respectively;SEQ ID NOs:6 and 5, respectively;SEQ ID NOs:8 and 7, respectively;SEQ ID NOs: 12 and 11, respectively;SEQ ID NOs: 14 and 13, respectively;SEQ ID NOs:42 and 41, respectively;SEQ ID NOs:44 and 43, respectively;SEQ ID NOs:52 and 51, respectively;SEQ ID NOs:54 and 53, respectively;SEQ ID NOs:56 and 55, respectively;SEQ ID NOs:46 and 45, respectively;SEQ ID NOs:48 and 47, respectively;SEQ ID NOs:50 and 49, respectively;SEQ ID NOs:82 and 81, respectively;SEQ ID NOs:80 and 79, respectively;SEQ ID NOs:58 and 57, respectively;SEQ ID NOs:60 and 59, respectively;SEQ ID NOs:62 and 61, respectively;SEQ ID NOs:64 and 63, respectively;SEQ ID NOs:66 and 65, respectively;SEQ ID NOs:68 and 67, respectively;SEQ ID NOs:70 and 69, respectively;SEQ ID NOs:72 and 71, respectively;SEQ ID NOs:74 and 73, respectively;SEQ ID NOs:76 and 75, respectively;SEQ ID NOs:78 and 77, respectively;SEQ ID NOs: 112 and 111, respectively;SEQ ID NOs:102 and 101, respectively;SEQ ID NOs: 104 and 103, respectively;SEQ ID NOs: 106 and 105, respectively;SEQ ID NOs: 108 and 107, respectively;SEQ ID NOs: 110 and 109, respectively;SEQ ID NOs:84 and 83, respectively;SEQ ID NOs:86 and 85, respectively;SEQ ID NOs:88 and 87, respectively;SEQ ID NOs:90 and 89, respectively;SEQ ID NOs:92 and 91, respectively;SEQ ID NOs:94 and 93, respectively;SEQ ID NOs:96 and 95, respectively;SEQ ID NOs:98 and 97, respectively;SEQ ID NOs: 100 and 99, respectively;SEQ ID NOs: 114 and 113, respectively;SEQ ID NOs: 120 and 119, respectively;SEQ ID NOs: 128 and 127, respectively;SEQ ID NOs: 130 and 129, respectively;SEQ ID NOs: 132 and 131, respectively;SEQ ID NOs: 134 and 133, respectively;SEQ ID NOs: 136 and 135, respectively;SEQ ID NOs: 138 and 137, respectively;SEQ ID NOs: 140 and 139, respectively;SEQ ID NOs: 142 and 141, respectively;SEQ ID NOs: 144 and 143, respectively;SEQ ID NOs:146 and 145, respectively;SEQIDN0s:116 and 115, respectively;SEQ ID NOs: 118 and 117, respectively;SEQ ID NOs: 122 and 121, respectively;SEQ ID NOs: 124 and 123, respectively;SEQ ID NOs: 126 and 125, respectively; orSEQ ID NOs: 193 and 188, respectively.
243. The conjugate or salt of any one of claims 226 to 242, wherein the antibody or portion thereof comprises a heavy chain variable domain (Vh) and a light chain variable domain (Vl), wherein the Vh and the Vl comprise:SEQ ID NOs: 148 and 147, respectively;SEQ ID NOs: 10 and 9, respectively;SEQ ID NOs: 16 and 15, respectively;SEQ ID NOs: 18 and 17, respectively;SEQ ID NOs:20 and 19, respectively;SEQ ID NOs:26 and 25, respectively;SEQ ID NOs:30 and 29, respectively;SEQ ID NOs: 112 and 111, respectively;SEQ ID NOs: 110 and 109, respectively;SEQ ID NOs:86 and 85, respectively;SEQ ID NOs: 128 and 127, respectively;SEQ ID NOs: 122 and 121, respectively; orSEQ ID NOs: 193 and 188, respectively.
244. The conjugate or salt of any one of claims 242 to 243, wherein the antibody comprises a human IgGl constant region.
245. The conjugate or salt of any one of claims 242 to 244, wherein the human IgGi constant region comprises SEQ ID NO:201, optionally without the C-terminal lysine.
246. The conjugate or salt of any one of claims 242 to 245, wherein the antibody comprises a human light chain constant region that comprises SEQ ID NO: 199.
247. The conjugate or salt of any one of claims 242 to 246, wherein the PTK7 antibody is optionally without the C-terminal lysine.
248. The conjugate or salt of any one of claims 204 to 247, wherein the DAR is selected from about 1 to about 8.
249. The conjugate or salt of any one of claims 204 to 247, wherein the DAR is about 8.
250. A pharmaceutical composition comprising a conjugate of any one of claims 204 to 249 and a pharmaceutically acceptable excipient.
251. A method of treating a subject with a disease or disorder, comprising administering to the subject in need thereof a conjugate of any one of claims 204 to 249 or a pharmaceutical composition of claim 250.
252. The method of claim 251, wherein the disease or disorder is a cancer.
253. A method of treating a subject with a cancer, comprising administering to the subject in need thereof a conjugate of any one of claims 204 to 249 or a pharmaceutical composition of claim 250.
254. A method of treating a subject with a PTK7-positive cancer, comprising administering to the subject in need thereof a conjugate of any one of claims 204 to 249 or a pharmaceutical composition of claim 250.
255. The method of any one of claims 252 to 254, wherein the cancer is selected from: melanoma, skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cellanaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV-associated T cell leukemia / lymphoma), or mesothelioma. In certain embodiments, the cancer is selected from the group consisting of head and neck cancer, bone cancer (e.g., osteosarcoma), Ewing sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple negative breast cancer), melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and chronic myelogenous leukemia. In particular embodiments, the cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, hepatic cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft-tissue sarcoma, bladder cancer, prostate cancer, renal cancer, and melanoma.
256. The method of any one of claims 252 to 254, wherein the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer.
257. The method of any one of claims 252 to 254, wherein the cancer is cell lymphoma.
258. The method of any one of claims 252 to 254, wherein the cancer is non-small cell lungcancer.
259. The method of any one of claims 252 to 254, wherein the cancer is large-cell lung cancer.
260. The method of any one of claims 252 to 254, wherein the cancer is breast cancer.
261. The method of any one of claims 252 to 254, wherein the cancer is small-cell lungcancer.
262. Use of a conjugate, for treating a subject with a disease or disorder, comprising administering to the subject in need thereof a conjugate of any one of claims 204 to 249 or a pharmaceutical composition of claim 250.
263. The use of claim 262, wherein the disease or disorder is cancer.