NZ789089A

NZ789089A - Anti-EGFR antibody drug conjugates

Info

Publication number: NZ789089A
Application number: NZ789089A
Authority: NZ
Inventors: Erwin R Boghaert; Milan Bruncko; Andrew S Judd; Andrew C Phillips; Andrew J Souers
Original assignee: Abbvie Inc
Priority date: 2016-06-08
Filing date: 2017-06-07
Publication date: 2022-07-01

Abstract

The invention relates to anti-Epidermal Growth Factor Receptor (EGFR) antibody drug conjugates (ADC’s) which inhibit Bcl-xL., including compositions and methods of using said ADC’s.

Description

ANTI-EGFR ANTIBODY DRUG CONJUGATES D APPLICATIONS This application is a divisional of New Zealand Patent Application No. 749053 (the national phase application of ) and claims priority to U.S. Provisional Application No. 62/347,416, filed on 8 June 2016, the entire ts of each of which are expressly incorporated herein by reference.

CE LISTING The t application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on 2 June 2017, is named 117813-13420 SL.txt and is 2 bytes in size.

OUND OF THE INVENTION The human epidermal growth factor or (also known as HER-I or Erb-Bl, and referred to herein as "EGFR") is a 170 kDa transmembrane receptor encoded by the c-erbB protooncogene, and exhibits intrinsic tyrosine kinase activity (Modjtahedi et al., Br. J. Cancer 73:228-235 (1996); Herbst and Shin, Cancer 94:1593-1611 ). SwissProt database entry P00533 es the ce of human EGFR. EGFR regulates numerous cellular processes via tyrosine-kinase mediated signal transduction pathways, including, but not limited to, activation of signal transduction pathways that control cell proliferation, differentiation, cell survival, apoptosis, angiogenesis, mitogenesis, and metastasis (Atalay et al., Ann. Oncology 14:1346-1363 (2003); Tsao and Herbst, Signal 4:4-9 (2003); Herbst and Shin, Cancer 94:1593-1611 (2002); Modjtahedi et al., Br. J. Cancer 73:228-235 (1996)).

Known ligands of EGFR include EGF, GF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding by EGFR triggers receptor homo- and/or dimerization and autophosphorylation of key cytoplasmic residues. The phosphorylated EGFR recruits adapter proteins like GRB2 which in turn activate complex downstream signaling cascades, including at least the following major downstream signaling cascades: the F-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC, and STATs modules. This autophosphorylation also elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains.

These downstream signaling proteins initiate l signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to cell proliferation. Ligand binding by EGFR may also activate the pa-B signaling cascade. Ligand binding also directly orylates other proteins like RGS16, activating its GTPase activity and potentially coupling the EGF receptor ing to G protein-coupled receptor signaling. Ligand binding also phosphorylates MUCI and increases its interaction with SRC and CTNNBI/beta-catenin.

Claims

We claim:

1. An anti-human Epidermal Growth Factor Receptor (hEGFR) antibody drug conjugate (ADC) comprising a drug linked to an anti-human Epidermal Growth Factor (hEGFR) antibody via a linker, wherein the drug is a Bcl-xL inhibitor according to structural formula (Ila), (lib), (Ile), or (Ild): (Ila) (Ilb) (Ile) (Ild) wherein: z2b R 12' �o z2b R'/ ......._ HN �o �o R' z2a' '# \ ", 4Q1 1 N R R 11b R 11a R11a R1a 1 707 N� J---N, I -"NV JVVv I N J-__:;,- N H N ;,_NH Ob and \___gN and is optionally substituted with one or more substituents independently selected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C1 4alkoxy, amino, cyano and halomethyl; CO� (N� t'1 N J �� J,_, , = , N�/�/ �/]� Error! Bookmark not defined., """" , = (]1 �Ny N2} / ____,Ny N;;-�� /_ ""i.i.. ""i.i.. and , or an N-oxide thereof, and is optionally substituted with one or more substituents independently selected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C1 4alkoxy, amino, cyano and halomethyl, wherein the R 12 -Z2 b-, R' -Z2 b-, #-N(R4 )-R 1 3 -Z2 b-, or# R' -Z2 b - substituents are attached to Ar2 at any Ar2 atom capable of being substituted; Z 1 is selected from N, CH, C-halo, C-CH3 and C-CN; Z 2 a and z 2 b are each , independently from one another, selected from a bond, NR6 , CR6 aR6 \ 0, S, S(O), S(Oh, -NR6C(O)-,-NR6 aC(O)NR6 b-, and -NR6C(O)O-; R, ;,; \�X ¼e,:} m � X ¼e,:}, whereill #, whe,e auached lo R', is auached lo R' at any R' atom capable of being substituted; X' is selected at each occurrence from -N(R1 0)- , -N(R1 0)C(O)-, -N(R1 0)S(Oh-, -S(OhN(R1 0)-, and ; n is selected from 0-3; R 1 0 is independently selected at each occurrence from hydrogen, lower alkyl, heterocycle, aminoalkyl, G-alkyl, and -(CH2h-O-(CH2h-O-(CH2h-NH2; G at each occurrence is independently selected from a polyol, a polyethylene glycol with between 4 and 30 repeating units, a salt and a moiety that is charged at physiological pH; 708 SPa is independently selected at each occurrence from oxygen, -S(OhN(H)-, -N(H)S(O)r, -N(H)C(O)-, -C(O)N(H) -, -N(H)- , arylene, heterocyclene, and optionally substituted methylene; wherein methylene is optionally substituted with one or more of -NH(CH2hG, NH2, C1 8alkyl, and carbonyl; m 2 is selected from 0-12; R 1 is selected from hydrogen, methyl, halo, halomethyl, ethyl, and cyano; R 2 is selected from hydrogen, methyl, halo, halomethyl and cyano; R 3 is selected from hydrogen, methyl, ethyl, halomethyl and haloethyl; R 4 is selected from hydrogen, lower alkyl and lower heteroalkyl or is taken together with an atom of R 1 3 to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms; R 6 , R 6a and R 6b are each, independent from one another, selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocyclyl, or are taken together with an atom from R 4 and an atom from R 1 3 to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms; R 11a and R 11b are each, independently of one another, selected from hydrogen, halo, methyl, ethyl, halomethyl, hydroxyl, methoxy, CN, and SCH3 ; R 12 is optionally R' or is selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; R 1 3 is selected from optionally substituted C1 8 alkylene, optionally substituted heteroalkylene, optionally substituted heterocyclene, and optionally substituted cycloalkylene; and # represents the point of attachment to a linker L; wherein the hEGFR antibody has the following characteristics: binds to an epitope within the amino acid sequence CGADSYEMEEDGVRKC (SEQ ID NO: 45) or competes with a second anti-hEGFR antibody for binding to epidermal growth factor receptor variant III (EGFRvIII) (SEQ ID NO: 33) in a competitive binding assay, wherein the second anti-EGFR antibody comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: I and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 5; and binds to EGFR(l-525) (SEQ ID NO: 47) with a dissociation constant (Kct) of about Ix 10 6 Md less, as determined by surface plasmon resonance.

2. The ADC of claim 1, which is a compound according to structural formula (I): (I) ( D-L-LKtAb wherein: D is the Bcl-xL inhibitor drug of formula (Ila), (Ilb ), (Ile) or (Ild); L is the linker; Ab is the anti-hEGFR antibody; 709 LK represents a covalent linkage linking the linker (L) to the anti-hEGFR antibody (Ab); and m is an integer ranging from I to 20.

3. The ADC of claim I or 2, wherein the Bcl-xL inhibitor is selected from the group consisting of the following compounds modified in that the hydrogen corresponding to the # position of structural formula (Ila), (Ilb), (Ile), or (Ild) is not present forming a monoradical: 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl][l-( { 3-[2-( { 2-[2- ( carboxymethoxy)ethoxy ]ethyl }amino )ethoxy ]-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl} methyl)methylIH-pyrazolyl]pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 2-{ [ (2-{ [2-( { 3-[( 4-{ 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl }oxy)ethyl]amino }ethyl)sulfonyl]amino }deoxy-D-glucopyranose; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ ( 4-{ [ (3R,4R,5 S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyran yl] methyl} benzyl)amino ]ethoxy} tricyclo[3.3. l .13, 7]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (3-sulfopropyl)amino ]ethoxy} tricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl]{ 1-[ (3-{ 2-[ (2,3- dihydroxypropyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 2-( { [ 4-( { [2-( {3-[( 4-{ 6-[8-(l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l .13 ' 7 ]dec-lyl }oxy)ethyl]amino} methyl)phenyl]sulfonyl }amino )deoxy-beta-D-glucopyranose; 8-( 1,3-benzothiazolylcarbamoyl){ 6-carboxy[l-( { 3-[2-( { 2-[l-(beta-D-glucopyranuronosyl) IH-1,2,3-triazolyl]ethyl }amino )ethoxy ]-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl} methyl)methyl-IHpyrazolyl]pyridinyl }-1,2,3,4-tetrahydroisoquinoline; 3-[ 1-( { 3-[2-(2-{ [ 4-(beta-D-allopyranosyloxy) benzyl] amino }ethoxy )ethoxy ]-5, 7- dimethyltricyclo[3 .3. l. l 3 ' 7 ]dec-l-yl} methyl)methyl- IH-pyrazolyl][8-( 1,3-benzothiazol ylcarbamoy I)-3 ,4-dihydroisoquinolin-2( I H)-y I ]pyridinecarboxy lie acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( IH)-yl]( 1-{ [3,5-dimethyl(2- { 2-[ (2-sulfoethyl)amino ]ethoxy }ethoxy)tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyl-IH-pyrazol yl)pyridinecarboxylic acid; 710 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (2-phosphonoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine2-carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ methyl(3-sulfo-L-alanyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (3-phosphonopropyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (3-sulfo-L-alanyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3,5-dimethyl(2- { 2-[ (3-phosphonopropyl)amino ]ethoxy }ethoxy)tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyl-l H-pyrazol yl)pyridinecarboxylic acid; 3-{ 1-[ (3-{ 2-[L-alpha-aspartyl(methyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( lH)-yl]pyridinecarboxylic acid; 6-{ 4-[( {2-[2-(2-aminoethoxy)ethoxy ]ethyl }[2-( {3-[( 4-{ 6-[8-(l,3-benzothiazolylcarbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl]carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7- dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl }oxy)ethyl]amino )methyl]benzyl }-2,6-anhydro-L-gulonic acid; 4-( { [2-( { 3-[( 4-{ 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l .13 ' 7 ]dec-lyl }oxy)ethyl]amino }methyl)phenyl hexopyranosiduronic acid; 6-[l-( l,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{ 1-[ (3,5-dimethyl{ 2- [(2-phosphonoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine2-carboxylic acid; 6-[l-( l,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{ 1-[ (3,5-dimethyl{ 2- [methyl(3-sulfo-L-alanyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl] methyl-1H-pyrazolyl }[8-([ 1,3 ]thiazolo[ 5,4-b ]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2( lH) yl]pyridinecarboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl] methyl-1H-pyrazolyl }[8-([ 1,3 ]thiazolo[ 4,5-b ]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2( lH) yl]pyridinecarboxylic acid; 711 6-[l-( l,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{ 1-[ (3,5-dimethyl{ 2- [(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ (2- carboxyethyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (3-phosphonopropyl)(piperidinyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1Hpyrazolyl }pyridinecarboxylic acid; 3-{ 1-[ (3-{ 2-[D-alpha-aspartyl(methyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( lH)-yl]pyridinecarboxylic acid; 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3-(2-{ [1- ( carboxymethyl)piperidinyl]amino }ethoxy)-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyllH-pyrazolyl)pyridinecarboxylic acid; N-[(5S)amino{ [2-( { 3-[( 4-{ 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( lH)-yl]carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l .13 ' 7 ]dec-lyl }oxy )ethyl] (methyl)amino }oxohexyl]-N,N-dimethylmethanaminium; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [piperidinyl(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-(l,3-benzothiazolylcarbamoyl)(3-phosphonopropoxy)-3,4-dihydroisoquinolin-2(1H)-yl]- 3-[ 1-( { 3,5-dimethyl[2-(methylamino )ethoxy ]tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl} methyl)methyl-lH-pyrazol yl]pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3-(2-{ [N-(2- carboxyethyl)-L-alpha-aspartyl] amino }ethoxy)-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyllH-pyrazolyl)pyridinecarboxylic acid; 3-{ 1-[ (3-{ 2-[ (2-aminoethyl)(2-sulfoethyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( lH)-yl]pyridinecarboxylic acid; 6-[ 5-(2-aminoethoxy )( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl][ 1- ( { 3,5-dimethyl[2-(methylamino )ethoxy ]tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl} methyl)methyl-lH-pyrazol yl]pyridinecarboxylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl)naphthalenyl]{ l -[(3,5-dimethyl{ 2-[(3- sulfopropyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 712 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ (2- carboxyethyl)(piperidinyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1Hpyrazolyl }pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (3-sulfo-L-alanyl)(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ { 2-[ (2- carboxyethyl)amino ]ethyl }(2-sulfoethyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl] methyl-1H-pyrazolyl }pyridinecarboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(3-phosphonopropyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]- 5-methyl-1H-pyrazolyl }[8-([ l ,3]thiazolo[ 4,5-b ]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2( lH) yl]pyridinecarboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(3-phosphonopropyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]- 5-methyl-1H-pyrazolyl }[8-([ l ,3]thiazolo[ 5,4-b ]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2( lH) yl]pyridinecarboxylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl)( carboxymethoxy )-3 ,4-dihydroisoquinolin-2( 1 H)-yl][ 1- ( { 3,5-dimethyl[2-(methylamino )ethoxy ]tricyclo[3.3. l. l 3'7 ]dec-l-yl} methyl)methyl-lH-pyrazol yl]pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ (3- carboxypropyl)(piperidinyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyll H-pyrazoly I} pyridinecarbox ylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl)naphthalenyl]{ l -[(3,5-dimethyl{ 2-[(2- sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 3-{ 1-[ (3-{ 2-[L-alpha-aspartyl(2-sulfoethyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( lH)-yl]pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ ( 1,3- dihydroxypropanyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1Hpyrazolyl }pyridinecarboxylic acid; 6-[ 5-(2-aminoethoxy )( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ l - [ (3,5-dimethyl{ 2-[methyl(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1Hpyrazolyl }pyridinecarboxylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl){ 2-[ (2-sulfoethyl)amino ]ethoxy }-3,4-dihydroisoquinolin2( lH)-yl]{ l-[(3,5-dimethyl{ 2-[ methyl(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]- 5-methyl-1H-pyrazolyl }pyridinecarboxylic acid; 713 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3,5-dimethyl{ 2- [ (2-sulfoethyl) { 2-[(2-sulfoethyl)amino ]ethyl }amino ]ethoxy} tricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl]methyll H-pyrazoly 1} pyridinecarbox ylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl){ 2-[ (2-carboxyethyl)amino ]ethoxy }-3,4- dihydroisoquinolin-2( l H)-yl]{ l-[(3,5-dimethyl{ 2-[methyl(2- sulfoethyl)amino ]ethoxy} tricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(3-phosphonopropyl)(piperidin yl)amino ]ethoxy} tricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }[8-([ l,3]thiazolo[ 4,5- b ]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]pyridinecarboxylic acid; 6-[ 4-( l,3-benzothiazolylcarbamoyl)-3,4-dihydro-2H-l ,4-benzoxazinyl]{ l-[(3,5-dimethyl { 2-[ (2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)(3-sulfopropoxy )-3 ,4-dihydroisoquinolin-2( lH)-yl][ 1 ( { 3,5-dimethyl[2-(methylamino )ethoxy ]tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl} methyl)methyl-lH-pyrazol yl]pyridinecarboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl] methyl-1H-pyrazolyl }[l-([l,3]thiazolo[ 4,5-b ]pyridinylcarbamoyl)-1,2,3,4-tetrahydroquinolin yl]pyridinecarboxylic acid; 3-{ 1-[ (3,5-dimethyl{ 2-[(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl] methyl-1H-pyrazolyl }[8-([ 1,3 ]thiazolo[ 4,5-b ]pyridinylcarbamoyl)naphthalenyl]pyridine carboxylic acid; ( l�) 1 ( { 2-[5-( 1 { [3-(2-aminoethoxy)-5,7-dimethyltricyclo[3 .3. l. l 3 ' 7 ]dec-l-yl]methyl }methyllH-pyrazoly 1 )carbox ypyridinyl ]( 1,3-benzothiazolylcarbamoyl )-1,2, 3, 4-tetrahydroisoquinolin5-y l} methyl)-1,5-anhydro-D-glucitol; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ (3- carboxypropyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l .13 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl)naphthalenyl]{ l -[(3,5-dimethyl{ 2-[(3- phosphonopropyl)amino ]ethoxy} tricyclo[3 .3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1 { [3-(2-{ [ 4-(beta-Dglucopyranosyloxy)benzyl]amino }ethoxy)-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyl-lHpyrazo 1y 1 )pyridinecarboxylic acid; 3-(1-{ [3-(2-{ [ 4-(beta-D-allopyranosyloxy)benzyl]amino }ethoxy)-5,7- dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyl-lH-pyrazolyl)[8-( 1,3-benzothiazol ylcarbamoy 1 )-3 ,4-dihydroisoquinolin-2( 1 H)-y 1 ]pyridinecarboxy lie acid; 714 3-{ 1-[ (3-{ 2-[ azetidinyl(2-sulfoethyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( l H)-yl]pyridinecarboxylic acid; 3-{ 1-[ (3-{ 2-[ (3-aminopropyl)(2-sulfoethyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin2( l H)-yl]pyridinecarboxylic acid; 6-[l-( l,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{ 1-[ (3-{ 2-[(2- carboxyethyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl]{ 1-[ (3-{ 2-[ (N6 ,N6 - dimethyl-L-lysyl)(methyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1Hpyrazolyl }pyridinecarboxylic acid; 3-{ 1-[ (3-{ 2-[ (3-aminopropyl)(methyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3 .3. l. l 3'7 ]dec-lyl)methyl]methyl-1H-pyrazolyl }[l-( l,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolin yl]pyridinecarboxylic acid; 3-{ 1-[ (3-{ 2-[ azetidinyl(methyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]- 5-methyl-1H-pyrazolyl }[ 1-( l,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]pyridine2-carboxylic acid; N 6 -(37-oxo-2,5,8, 11, 14, 17,20,23,26,29 ,32,35-dodecaoxaheptatriacontanyl)-L-lysyl-N-[2-( { 3- [ ( 4-{ 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( 1 H)-yl]carboxypyridinyl } methyl-l H-pyrazol-l -yl)methyl]-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl }oxy)ethyl]-L-alaninamide; methyl 6-[ 4-(3-{ [2-( { 3-[( 4-{ 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH) yl]carboxypyridinyl }methyl-l H-pyrazol-l-yl)methyl]-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-lyl }oxy)ethyl]amino }propyl)-l H-1,2,3-triazol-l-yl]deoxy-beta-L-glucopyranoside; 6-[8-( 1,3-benzothiazolylcarbamoyl)naphthalenyl]{ 1-[ (3-{ 2-[ (2- carboxyethyl)amino ]ethoxy }-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[ 5-( 1,3-benzothiazolylcarbamoyl)quinolinyl]{ 1-[ (3,5-dimethyl{ 2-[ (2- sulfoethyl )amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[ 4-( 1,3-benzothiazolylcarbamoyl)quinolinyl]{ 1-[ (3,5-dimethyl{ 2-[(2- sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[ 5-( 1,3-benzothiazolylcarbamoyl)quinolinyl]{ 1-[ (3-{ 2-[ (2-carboxyethyl)amino ]ethoxy }- 5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl)methyl]methyl-1H-pyrazolyl }pyridinecarboxylic acid; 715 6-[ 1-( l ,3-benzothiazolylcarbamoyl)-5,6-dihydroimidazo[ 1,5-a ]pyrazin-7 (8H)-yl ]{ 1-[ (3,5- dimethyl-7 -{ 2-[(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 8-( 1,3-benzothiazolylcarbamoyl){ 6-carboxy[l-( { 3-[2-( { 3-[l-(beta-D-glucopyranuronosyl) lH-1,2,3-triazolyl]propyl} amino )ethoxy ]-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl} methyl)methyl-lHpyrazolyl]pyridinyl }-1,2,3,4-tetrahydroisoquinoline; 6-[7-( 1,3-benzothiazolylcarbamoyl)-lH-indolyl]{ l-[(3,5-dimethyl{ 2-[(2- sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec- l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( 1,3-benzothiazolylcarbamoyl)[3-(methylamino )propyl]-3,4-dihydroisoquinolin-2( lH) yl]{ l-[(3,5-dimethyl{ 2-[(2-sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec-l-yl)methyl]methyl-1Hpyrazolyl }pyridinecarboxylic acid; 5-{ [2-( { 3-[( 4-{ 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl }oxy)ethyl]amino }deoxy-D-arabinitol; 1-{ [2-( { 3-[( 4-{ 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l .13 ' 7 ]dec-lyl }oxy)ethyl]amino }-1,2-dideoxy-D-arabino-hexitol; 6-[ 4-( 1,3-benzothiazolylcarbamoyl)isoquinolinyl]{ l-[(3,5-dimethyl{ 2-[ (2- sulfoethyl)amino ]ethoxy} tricyclo[3.3. l. l 3 ' 7 ]dec- l-yl)methyl]methyl-1H-pyrazolyl }pyridine carboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3-(2-{ [3-hydroxy2-(hydroxymethyl)propyl] amino }ethoxy)-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-l-yl]methyl }methyl-lHpyrazo 1y I )pyridinecarboxylic acid; 1-{ [2-( { 3-[( 4-{ 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l .13 ' 7 ]dec-lyl }oxy)ethyl]amino }-1,2-dideoxy-D-erythro-pentitol; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3,5-dimethyl(2- { [(2S,3S)-2,3,4-trihydroxybutyl]amino }ethoxy)tricyclo[3.3. l .l 3 ' 7 ]dec-l-yl]methyl }methyl-lH-pyrazol yl)pyridinecarboxylic acid; 6-[8 -( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3-(2- { [(2S,3S,4R,5R,6R)-2,3,4,5,6,7-hexahydroxyheptyl]amino }ethoxy)-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl]methyl }methyl-lH-pyrazolyl)pyridinecarboxylic acid; 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[(3-{ 2-[( { 3-[( 1,3- dihydroxypropanyl)amino ]propyl} sulfonyl)amino ]ethoxy }-5, 7-dimethyltricyclo[3.3. l. l 3 ' 7 ]dec-lyl)methyl]methyl-1H-pyrazolyl} pyridinecarboxylic acid; 716 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]{ 1-[ (3-{ 2-[ (3-{ [ l ,3- dihydroxy(hydroxymethyl)propanyl] amino }oxopropyl)amino ]ethoxy }-5, 7- dimethyltricyclo[3 .3. l. l 3'7 ]dec-l -yl)methyl]methyl-1H-pyrazolyl }pyridinecarboxylic acid; 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3-(2-{ [ (3S)-3,4- dihydroxybutyl] amino }ethoxy)-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl]methyl }methyl-lH-pyrazol yl)pyridinecarboxylic acid; 4-( { [2-( { 3-[( 4-{ 6-[8-( l ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl] carboxypyridinyl }methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3. l. l 3'7 ]dec-lyl }oxy)ethyl]amino }methyl)phenyl beta-D-glucopyranosiduronic acid; 3-{ [2-( { 3-[( 4-{ 6-[8-( 1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridinyl } methyl-lH-pyrazol-l-yl)methyl]-5, 7-dimethyltricyclo[3.3. l. l 3'7 ]dec-l-yl }oxy)ethyl]amino }propyl beta-Dglucopyranosiduronic acid; 6-[ 4-( 1,3-benzothiazolylcarbamoyl)oxidoisoquinolinyl][l-( { 3,5-dimethyl[2- (methylamino )ethoxy ]tricyclo[3.3. l. l 3'7 ]dec-l-yl} methyl)methyl-lH-pyrazolyl]pyridinecarboxylic acid; 6-{ 8-[ ( l,3-benzothiazolyl)carbamoyl]-3,4-dihydroisoquinolin-2( lH)-yl }{ l-[(3,5-dimethyl { 2-[ (2-sulfoethyl)amino ]acetamido} tricyclo[3.3. l. l 3'7 ]decan-l-yl)methyl]methyl-1H-pyrazol yl} pyridinecarboxylic acid; 6-[8-( l,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl]( 1-{ [3,5-dimethyl( { 2- [(2-sulfoethyl)amino ]ethyl }sulfanyl)tricyclo[3.3. l. l 3'7 ]dec-l-yl]methyl }methyl-lH-pyrazol yl)pyridinecarboxylic acid; and 6-{ 8-[ ( l,3-benzothiazolyl)carbamoyl]-3,4-dihydroisoquinolin-2( lH)-yl }{ l-[(3,5-dimethyl { 3-[ (2-sulfoethyl)amino ]propyl} tricyclo[3.3. l. l 3'7 ]decan-l-yl)methyl]methyl-1H-pyrazolyl} pyridine2-carboxylic acid.

4. The ADC of claim 2, selected from the group consisting of formulae i-vi: O<::::,,NH2 J Ab NH S O''loH H \ o H o�o m ) �N�N�N� Cf O £ 7 o� 0 H)-___ 0 N,t{: 4 0� 0 HN O �: J...-s No 717 (i), - OH OH 6H OH OH - OH OH 6H 718 Ab A b m (ii), (iii), (iv), (v), and (vi), wherein m is an integer from 1 to 6; optionally 2 to 6.

5. The ADC of any one of claims 1- 4, wherein the anti-hEGFR antibody comprises a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 11, and a heavy chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 10; a light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 8, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 6; or a light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 40, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, and a light chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 38; and a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 37, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 36, and a heavy chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 35; or a light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 8, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 6; and a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 16, or a light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 25, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 24, and a light chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 23; and a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 18, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 16, or a light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 28, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 27, and a light chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 26; and a heavy chain CDR3 719 domain comprising the amino acid sequence set forth in SEQ ID NO: 19, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 11, and a heavy chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 10.

6. The ADC of any one of claims 1-4, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 5.

7. The ADC of any one of claims 1-4, wherein the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 13.

8. The ADC of any one of claims 1-4, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and a light chain variable region comprising an amino acid sequence selected from the group consisting of 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 79.

9. The ADC of any one of claims 1-4, wherein the antibody comprises a heavy chain CDR set (CDRl, CDR2, and CDR3) selected from the group consisting of SEQ ID NOs: 10, 11, and 12; SEQ ID NOs: 16, 17, and 18; SEQ ID NOs: 10, 11, and 19; SEQ ID NOs: 20, 11, and 12; SEQ ID NOs: 21, 3, and 22; SEQ ID NOs: 16, 17, and 19; SEQ ID NOs: 2, 3, and 4; SEQ ID NOs: 10, 3, and 12; SEQ ID NOs: 80, 11, and 18; SEQ ID NOs: 80, 3, and 18; SEQ ID NOs: 20, 3, and 12; SEQ ID NOs: 80, 11, and 12; and SEQ ID NOs: 81, 11, and 22; and a light chain CDR set (CDRl, CDR2, and CDR3) selected from the group consisting of SEQ ID NOs: 6, 7, and 8; SEQ ID NOs: 23, 24, and 25; SEQ ID NOs: 26, 27, and 28; SEQ ID NOs: 29, 30, and 31; SEQ ID NOs: 6, 7, and 84; SEQ ID NOs: 82, 83, and 31; and SEQ ID NOs: 82, 27, and 85, wherein the antibody does not comprise both the heavy chain CDR set of SEQ ID NOs: 2, 3, and 4, and the light chain CDR set of SEQ ID NOs: 6, 7, and 8.

10. The ADC of any one of claims 1-4, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 64, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 65.

11. The ADC of any one of claims 1-4, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 73; or a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 74, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 75.

12. A pharmaceutical composition comprising an effective amount of an ADC according to any one of claims 1-11, and a pharmaceutically acceptable carrier. 720

13. A pharmaceutical composition comprising an ADC mixture comprising a plurality of the ADC of any one of claims 1-11, and a pharmaceutically acceptable carrier.

14. A method for treating cancer, comprising administering a therapeutically effective amount of the ADC of any one of claims 1-11 to a subject in need thereof.

15. A method for inhibiting or decreasing solid tumor growth in a subject having a solid tumor, said method comprising administering an effective amount of the ADC of any one of claims 1-11 to the subject having the solid tumor, such that the solid tumor growth is inhibited or decreased.

16. The method of claim 14 or 15, wherein the ADC is administered in combination with an additional agent or an additional therapy.

17. A process for the preparation of an ADC according to structural formula (I): (I) ( D-L--LKtAb wherein: Dis the Bcl-xL inhibitor drug of formula (Ila), (Ilb ), (Ile), or (Ild); L is the linker; Ab is an hEGFR antibody; LK represents a covalent linkage linking linker L to antibody Ab; and m is an integer ranging from I to 20; the process comprising: treating an antibody in an aqueous solution with an effective amount of a disulfide reducing agent at 30-40 °C for at least 15 minutes, and then cooling the antibody solution to 20-27 °C; adding to the reduced antibody solution a solution of water/dimethyl sulfoxide comprising a synthon selected from the group of 2.1 to 2.17 6 (Table 5); adjusting the pH of the solution to a pH of 7 .5 to 8.5; allowing the reaction to run for 48 to 80 hours to form the ADC; wherein the mass is shifted by 18 ± 2 amu for each hydrolysis of a succinimide to a succinamide as measured by electron spray mass spectrometry; and wherein the ADC is optionally purified by hydrophobic interaction chromatography.

18. An ADC prepared by the process of claim 17.

19. An anti-human Epidermal Growth Factor Receptor (hEGFR) antibody drug conjugate (ADC) selected from the group consisting of formulae (i), (ii), (iii), (iv), (v), or (vi): 721 OH 6H OH 722 Ab (i), Ab (ii), Ab (iii), and wherein m is an integer from 1 to 6; optionally 2 to 6; and wherein Ab is either (iv), (v), and (vi), an anti-hEGFR antibody comprising a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 11, and a heavy chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 10; a comprising light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 8, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chain CDRl domain comprising the amino acid sequence set forth in SEQ ID NO: 6: or 723 an anti-hEGFR antibody comprising a light chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 25, a light chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 24, and a light chain CDRI domain comprising the amino acid sequence set forth in SEQ ID NO: 23; and a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 18, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 17, and a heavy chain CDRI domain comprising the amino acid sequence set forth in SEQ ID NO: 16.

20. The ADC of claim 19, wherein the antibody is selected from the group consisting of an anti-hEGFR antibody comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 5; an anti-hEGFR antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 13; and an anti-hEGFR antibody comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 73.