Anti-HER2 Antibodies and Immunoconjugates

1 - 19 . (canceled)

20 . An immunoconjugate comprising an antibody of and a cytotoxic agent, wherein the antibody comprises (i) a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10; (ii) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23; or (iii) a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18.

21 . An immunoconjugate having the formula Ab-(L-D)p, wherein:

(a) Ab is an antibody of comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15, HVR-H2 comprising the amino acid sequence of SEQ ID NO:16, HVR-H3 comprising the amino acid sequence of SEQ ID NO:17, HVR-L1 comprising the amino acid sequence of SEQ ID NO:12, HVR-L2 comprising the amino acid sequence of SEQ ID NO:13, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:14; (ii) a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10; (iii) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23; or (iv) a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18;

(b) L is a linker;

(c) D is a cytotoxic agent; and

(d) p ranges from 1-8.

22 . The immunoconjugate of claim 20 , wherein the cytotoxic agent is selected from an auristatin, a maytansinoid, a calicheamicin, a pyrrolobenzodiazepine, a nemorubicin derivative, and a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI).

23 . The immunoconjugate of claim 21 , wherein the cytotoxic agent is a pyrrolobenzodiazepine of Formula A:

wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;

R 2 is independently selected from H, OH, ═O, ═CH 2 , CN, R, OR, ═CH—R D , ═C(R D ) 2 , O—SO 2 —R, CO 2 R and COR, and optionally further selected from halo or dihalo, wherein R D is independently selected from R, CO 2 R, COR, CHO, CO 2 H, and halo;

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;

R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;

Q is independently selected from O, S and NH;

R 11 is either H or R, or Q is O and R 11 is SO 3 M, where M is a metal cation;

R and R′ are each independently selected from optionally substituted C 1-8 alkyl, C 3-8 heterocyclyl and C 5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;

R 12 , R 16 , R 19 and R 17 are as defined for R 2 , R 6 , R 9 and R 7 respectively;

R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings that are optionally substituted; and

X and X′ are independently selected from O, S and N(H).

24 . The immunoconjugate of claim 23 , wherein D has the structure:

wherein n is 0 or 1.

25 . The immunoconjugate of claim 21 , wherein the cytotoxic agent is a nemorubicin derivative.

26 . The immunoconjugate of claim 25 , wherein the cytotoxic agent has a structure selected from:

27 . The immunoconjugate of claim 21 , wherein the cytotoxic agent comprises a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI).

28 . The immunoconjugate of claim 27 , wherein the cytotoxic agent has the formula:

where

R 1 is selected from H, P(O) 3 H 2 , C(O)NR a R b , or a bond to L;

R 2 is selected from H, P(O) 3 H 2 , C(O)NR a R b , or a bond to L;

R a and R b are independently selected from H and C 1 -C 6 alkyl optionally substituted with one or more F,

or R a and R b form a five or six membered heterocyclyl group;

T is a tether group selected from C 3 -C 12 alkylene, Y, (C 1 -C 6 alkylene)-Y—(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-Y—(C 1 -C 6 alkylene)-Y—(C 1 -C 6 alkylene), (C 2 -C 6 alkenylene)-Y—(C 2 -C 6 alkenylene), and (C 2 -C 6 alkynylene)-Y—(C 2 -C 6 alkynylene);

where Y is independently selected from O, S, NR 1 , aryl, and heteroaryl;

where alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with F, OH, O(C 1 -C 6 alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1 -C 6 alkyl, where alkyl is optionally substituted with one or more F;

or alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with a bond to L;

D′ is a drug moiety selected from:

where the wavy line indicates the site of attachment to T;

X 1 and X 2 are independently selected from O and NR 3 , where R 3 is selected from H and C 1 -C 6 alkyl optionally substituted with one or more F;

R 4 is H, CO 2 R, or a bond to a linker (L), where R is C 1 -C 6 alkyl or benzyl; and

R 5 is H or C 1 -C 6 alkyl.

29 . The immunoconjugate of claim 28 , wherein the cytotoxic agent has a structure selected from:

30 . The immunoconjugate of claim 21 , wherein the linker is cleavable by a protease.

31 . The immunoconjugate of claim 21 , wherein the linker is acid-labile.

32 . The immunoconjugate of claim 31 , wherein the linker comprises hydrazone.

33 . The immunoconjugate of claim 21 , wherein the linker comprises a disulfide.

34 . The immunoconjugate of claim 21 having a structure selected from:

35 . The immunoconjugate of claim 21 having a formula selected from:

36 . The immunoconjugate of claim 21 , having a structure selected from:

37 . The immunoconjugate of claim 21 , wherein the cytotoxic agent comprises the structure:

38 . The immunoconjugate of claim 21 , wherein p ranges from 1.3-2 or from 2-5.

39 - 76 . (canceled)

77 . The immunoconjugate of claim 20 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23.

78 . The immunoconjugate of claim 20 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18.

79 . The immunoconjugate of claim 21 , wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10.

80 . The immunoconjugate of claim 21 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23.

81 . The immunoconjugate of claim 21 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18.

82 . The immunoconjugate of claim 21 , wherein the cytotoxic agent is selected from an auristatin, a maytansinoid, a calicheamicin, a pyrrolobenzodiazepine, a nemorubicin derivative, and a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI).