MONOCLONAL ANTIBODIES AGAINST HER2

1 - 52 . (canceled)

53 . A method for detecting the presence of human epidermal growth factor receptor 2 (HER2) in a sample comprising:

i) contacting the sample with an antibody which binds HER2 and which comprises a VH region comprising a CDR3 sequence selected from the group consisting of:

a) SEQ ID NO:133;

b) SEQ ID NO:11;

c) SEQ ID NO:130;

d) SEQ ID NO:136;

e) SEQ ID NO:139;

f) SEQ ID NO:142;

g) SEQ ID NO:148;

h) SEQ ID NO:52;

i) SEQ ID NO:145;

j) SEQ ID NO:154;

k) SEQ ID NO:151;

l) SEQ ID NO:4;

m) SEQ ID NO:18;

n) SEQ ID NO;25;

o) SEQ ID NO 31;

p) SEQ ID NO:38;

q) SEQ ID NO:48;

r) SEQ ID NO:59;

s) SEQ ID NO:66; and

t) SEQ ID NO:73; and

ii) analyzing whether a complex has been formed.

54 . The method of claim 53 , wherein the antibody comprises a VH region comprising CDR1, CDR2, CDR3 sequences selected from the group consisting of

a) SEQ ID NOs:131, 132, and 133, respectively;

b) SEQ ID NOs:9, 127 and 11, respectively;

c) SEQ ID NOs:128, 129 and 130, respectively;

d) SEQ ID NOs:134, 135 and 136, respectively;

e) SEQ ID NOs:137, 138 and 139, respectively;

f) SEQ ID NOs:140, 141 and 142, respectively;

g) SEQ ID NOs:146, 147 and 148, respectively;

h) SEQ ID NOs:149, 51 and 52, respectively;

i) SEQ ID NOs:143, 144 and 145, respectively;

j) SEQ ID NOs:152, 153 and 154, respectively; and

k) SEQ ID NOs:71, 150 and 151, respectively.

55 . The method of claim 54 , wherein the antibody comprises a VH region comprising CDR1, CDR2, CDR3 sequences selected from the group consisting of

a) SEQ ID NOs: 2, 3 and 4, respectively;

b) SEQ ID NOS: 9, 10 and 11, respectively;

c) SEQ ID NOs:16, 17 and 18, respectively;

d) SEQ ID NOS: 23, 24 and 25, respectively;

e) SEQ ID NOs:30, 163, and 31, respectively;

f) SEQ ID NOs: 36, 37 and 38, respectively:

g) SEQ ID NOS: 43, 44 and 45, respectively;

h) SEQ ID NOs:50, 51 and 52, respectively;

i) SEQ ID NOs: 57, 58 and 59, respectively;

j) SEQ ID NOs:64, 65 and 66, respectively; and

k) SEQ ID NOs: 71, 72 and 73, respectively.

56 . The method of claim 55 , wherein the antibody comprises a VH region and a VL region selected from the groups consisting of:

a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:2, 3 and 4, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:6, DAS, and SEQ ID NO:7, respectively;

b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:9, 10 and 11, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:13, AAS, and SEQ ID NO:14, respectively;

c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:16, 17 and 18, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:20, VAS, and SEQ ID NO:21, respectively;

d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:23, 24 and 25, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:27, AAS, and SEQ ID NO:28, respectively;

e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:30, 163 and 31, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:33, AAS, and SEQ ID NO:34, respectively;

f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:36, 37 and 38, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:40, DAS, and SEQ ID NO:41, respectively;

g) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:43, 44 and 45, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:47, AAS, and SEQ ID NO:48, respectively;

h) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:50, 51 and 52, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:54, AAS, and SEQ ID NO:55, respectively;

i) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:57, 58 and 59, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:60, AAS, and SEQ ID NO:61, respectively;

j) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:64, 65 and 66, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:68, DAS, and SEQ ID NO:69, respectively; and

k) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:71, 72 and 73, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:75, DAS, and SEQ ID NO:76, respectively.

57 . The method of claim 53 , wherein the antibody comprises a VH region and a VL region selected from the group consisting of:

a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;

b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;

c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;

d) a VH region comprising the sequence of SEQ ID NO:77 and a VL region comprising the sequence of SEQ ID NO:78;

e) a VH region comprising the sequence of SEQ ID NO:79 and a VL region comprising the sequence of SEQ ID NO:80;

f) a VH region comprising the sequence of SEQ ID NO:81 and a VL region comprising the sequence of SEQ ID NO:82;

g) a VH region comprising the sequence of SEQ ID NO:83 and a VL region comprising the sequence of SEQ ID NO:84;

h) a VH region comprising the sequence of SEQ ID NO:85 and a VL region comprising the sequence of SEQ ID NO:86;

i) a VH region comprising the sequence of SEQ ID NO:87 and a VL region comprising the sequence of SEQ ID NO:88;

j) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;

k) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:32;

l) a VH region comprising the sequence of SEQ ID NO:35 and a VL region comprising the sequence of SEQ ID NO:39;

m) a VH region comprising the sequence of SEQ ID NO:89 and a VL region comprising the sequence of SEQ ID NO:90;

n) a VH region comprising the sequence of SEQ ID NO:91 and a VL region comprising the sequence of SEQ ID NO:92;

o) a VH region comprising the sequence of SEQ ID NO:93 and a VL region comprising the sequence of SEQ ID NO:94;

p) a VH region comprising the sequence of SEQ ID NO:95 and a VL region comprising the sequence of SEQ ID NO:96;

q) a VH region comprising the sequence of SEQ ID NO:97 and a VL region comprising the sequence of SEQ ID NO:98;

r) a VH region comprising the sequence of SEQ ID NO:99 and a VL region comprising the sequence of SEQ ID NO:100;

s) a VH region comprising the sequence of SEQ ID NO:101 and a VL region comprising the sequence of SEQ ID NO:102;

t) a VH region comprising the sequence of SEQ ID NO:103 and a VL region comprising the sequence of SEQ ID NO:104;

u) a VH region comprising the sequence of SEQ ID NO:105 and a VL region comprising the sequence of SEQ ID NO:106;

v) a VH region comprising the sequence of SEQ ID NO:106 and a VL region comprising the sequence of SEQ ID NO:108;

w) a VH region comprising the sequence of SEQ ID NO:46 and a VL region comprising the sequence of SEQ ID NO:49;

x) a VH region comprising the sequence of SEQ ID NO:49 and a VL region comprising the sequence of SEQ ID NO:53;

y) a VH region comprising the sequence of SEQ ID NO:56 and a VL region comprising the sequence of SEQ ID NO:60;

z) a VH region comprising the sequence of SEQ ID NO:63 and a VL region comprising the sequence of SEQ ID NO:67;

aa) a VH region comprising the sequence of SEQ ID NO:70 and a VL region comprising the sequence of SEQ ID NO:74;

bb) a VH region comprising the sequence of SEQ ID NO:109 and a VL region comprising the sequence of SEQ ID NO:110;

cc) a VH region comprising the sequence of SEQ ID NO:111 and a VL region comprising the sequence of SEQ ID NO:112;

dd) a VH region comprising the sequence of SEQ ID NO:113 and a VL region comprising the sequence of SEQ ID NO:114;

ee) a VH region comprising the sequence of SEQ ID NO:115 and a VL region comprising the sequence of SEQ ID NO:116;

ff) a VH region comprising the sequence of SEQ ID NO:117 and a VL region comprising the sequence of SEQ ID NO:118;

gg) a VH region comprising the sequence of SEQ ID NO:119 and a VL region comprising the sequence of SEQ ID NO:120;

hh) a VH region comprising the sequence of SEQ ID NO:121 and a VL region comprising the sequence of SEQ ID NO:122;

ii) a VH region comprising the sequence of SEQ ID NO:123 and a VL region comprising the sequence of SEQ ID NO:124;

jj) a VH region comprising the sequence of SEQ ID NO:125 and a VL region comprising the sequence of SEQ ID NO:126; and

kk) a variant of any of said antibodies, wherein said variant preferably has at most 1,2 or 3 amino-acid modifications, more preferably amino-acid substitutions, such as conservative amino acid substitutions and substitutions where the new amino acid is one at the same position in an aligned sequence in FIG. 1 or 2 , particularly at positions indicated by “X” in the corresponding consensus sequence.

58 . The method of claim 53 , wherein the antibody has an EC50 value for binding to HER2-expressing cells lower than 0.80 μg/ml when determined as described in Example 12.

59 . The method of claim 53 , wherein the antibody induces ADCC when determined as described in Example 15.

60 . The method of claim 53 , wherein the antibody promotes ligand-independent proliferation of HER2-expressing cells less than F5 when determined as described in Example 16.

61 . The method of claim 53 , wherein the antibody inhibits ligand-independent proliferation of HER2-expressing cells when determined as described in Example 16.

62 . The method of claim 53 , wherein the antibody does not promote ligand-induced proliferation of HER2-expressing cells when determined as described in Example 17.

63 . The method of claim 53 , wherein the antibody inhibits ligand-induced proliferation of HER2-expressing cells when determined as described in Example 17.

64 . The method of claim 53 , wherein the antibody, when conjugated directly or indirectly to a therapeutic moiety such as a truncated form of the pseudomonas -exotoxin A, kills at least 49% of HER2-expressing cells when determined as described in Example 18.

65 . The method of claim 53 , wherein a higher amount of the antibody than trastuzumab is internalized by a HER2-expressing tumor cell-line when determined according to Example 18.

66 . The method of claim 53 , wherein the antibody is a full-length antibody.

67 . The method of claim 53 , wherein the antibody is a bispecific antibody.

68 . The method of claim 67 , wherein the bispecific antibody comprises an antigen-binding region of the antibody as defined in claim 1 , and a second antigen-binding site having a different binding specificity.

69 . The method of claim 67 , wherein the bispecific antibody comprises (i) a first antibody and a (ii) second antibody, wherein the first antibody is an antibody as defined in claim 1 , or an antibody comprising a VH region comprising a CDR3 sequence of SEQ ID NO: 168, and wherein the second antibody binds to a different epitope than the first antibody.

70 . The method of claim 69 , wherein the second antibody is a CD3 antibody.

71 . The method of claim 70 , wherein the CD3 antibody comprises a) a VH region comprising the sequence of SEQ ID NO:171 and a VL region comprising the sequence of SEQ ID NO:172; or b) a VH region comprising the sequence of SEQ ID NO: 173 and a VL region comprising the sequence of SEQ ID NO: 174.

72 . The method of claim 53 , wherein the antibody is conjugated to another moiety.

73 . The method of claim 72 , wherein the moiety is selected from the group consisting of taxol; cytochalasin B; gramicidin D; ethidium bromide; emetine; mitomycin; etoposide; tenoposide; vincristine; vinblastine; colchicin; doxorubicin; daunorubicin; dihydroxy anthracin dione; a tubulin-inhibitor; mitoxantrone; mithramycin; actinomycin D; 1-dehydrotestosterone; a glucocorticoid; procaine; tetracaine; lidocaine; propranolol; puromycin; calicheamicin or an analog or derivative thereof; an antimetabolite; an alkylating agent; an antibiotic; an antimitotic agent; a toxin; ribonuclease (RNase); DNase I, Staphylococcal enterotoxin A; pokeweed antiviral protein; diphtherin toxin; and Pseudomonas endotoxin.

74 . The method of claim 72 , wherein the moiety is selected from the group consisting of maytansine, calicheamicin, duocarmycin, rachelmycin (CC-1065), monomethyl auristatin E, monomethyl auristatin F or an analog, derivative, or prodrug of any thereof.

75 . The method of claim 72 , wherein the antibody is conjugated to a cytokine selected from the group consisting of IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b, IL-29, KGF, IFNα, IFNβ, IFNγ, GM-CSF, CD40L, Flt3 ligand, stem cell factor, ancestim, and TNFα.

76 . The method of claim 72 , wherein the antibody is conjugated to a radioisotope.