US 12,171,839 B2
Antibody drug conjugates for ablating hematopoietic stem cells
Anthony Edward Boitano, Waban, MA (US); Matthew Burger, Belmont, MA (US); Susan E. Cellitti, San Diego, CA (US); Michael P. Cooke, Boston, MA (US); Catrin Finner, Neuried (DE); Bernhard Hubert Geierstanger, Solano Beach, CA (US); Yunho Jin, San Diego, CA (US); Si Tuen Lee-Hoeflich, Lexington, MA (US); HongNgoc Thi Pham, San Mateo, CA (US); Siew Ho Schleyer, El Cerrito, CA (US); Kathrin Tissot, Neuried (DE); Tetsuo Uno, San Diego, CA (US); and Ben Wen, Encinitas, CA (US)
Assigned to Novartis AG, Basel (CH)
Filed by Novartis AG, Basel (CH)
Filed on Jun. 6, 2022, as Appl. No. 17/833,077.
Application 17/833,077 is a continuation of application No. 16/470,897, granted, now 11,357,864, previously published as PCT/IB2017/058159, filed on Dec. 19, 2017.
Claims priority of provisional application 62/437,622, filed on Dec. 21, 2016.
Claims priority of provisional application 62/520,854, filed on Jun. 16, 2017.
Prior Publication US 2022/0305134 A1, Sep. 29, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07K 16/00 (2006.01); A61K 38/07 (2006.01); A61K 38/12 (2006.01); A61K 47/68 (2017.01); C07K 16/28 (2006.01); C07K 16/46 (2006.01)
CPC A61K 47/6849 (2017.08) [A61K 38/07 (2013.01); A61K 38/12 (2013.01); A61K 47/68031 (2023.08); A61K 47/68033 (2023.08); A61K 47/6831 (2017.08); C07K 16/2803 (2013.01); C07K 2317/21 (2013.01); C07K 2317/55 (2013.01); C07K 2317/92 (2013.01)] 11 Claims
 
1. A conjugate having the structure of Formula (C):

OG Complex Work Unit Chemistry
wherein:
A is an antibody fragment that specifically binds to human cKIT;
y is an integer from 1 to 10;
R2 is C1-C6alkyl;
L20 is -L1R40;
Li is -((CH2)mO)p(CH2)mX1L4-, —((CH2)mO)p(CH2)mX2L4-, —((CH2)mO)p(CH2)m—, —(CH2)m—, —(CH2)mX1(CH2)m—, —(CH2)mNHC(═O)(CH2)m—, —(CH2)mNHC(═O)(CH2)mC(═O)NH(CH2)m—, —((CH2)mO)p(CH2)mNHC(═O)(CH2)m, —((CH2)mO)pCH2)mC(═O)NH(CH2)m—, X3X4C(═O)((CH2)mO)p(CH2)m—, —X3X4C(═O)(CH2)m—, —X3C(═O)(CH2)mNHC(═O)(CH2)m, —X3C(═O)(CH2)mNHC(═O)((CH2)mO)p(CH2)m—, —(CH2)mC(R7)2—, —(CH2)mC(R7)2SS(CH2)mNHC(═O)(CH2)m or —(CH2)mX3C(═O)(CH2)mNHC(═O)((CH2)mO)p(CH2)m—;
L4 is —((CH2)m;
X1 is

OG Complex Work Unit Chemistry
 where the * indicates attachment point to L4;
X2 is

OG Complex Work Unit Chemistry
 where the * indicates attachment point to L4;
X3 is

OG Complex Work Unit Chemistry
X4 is

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
R40 is

OG Complex Work Unit Chemistry
 —NR7C(═O)CH2—, —NHC(═O)CH2—, —S(═O)2CH2CH2—, —(CH2)2S(═O)2CH2CH2—, —NR7S(═O)2CH2CH2, —NR7C(═O)CH2CH2—, —NH—, —C(═O)—, —NHC(═O)—, —CH2NHCH2CH2—, —NHCH2CH2—, —S—,

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
each R7 is independently selected from H and C1-C6alkyl;
each R10 is independently selected from H, C1-C6alkyl, F, Cl, and —OH;
each R11 is independently selected from H, C1-C6alkyl, F, Cl, —NH2, —OCH3, —OCH2CH3, —N(CH3)2, —CN, —NO2 and —OH;
each R12 is independently selected from H, C1-6alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C1-4alkoxy substituted with —C(═O)OH and C1-4alkyl substituted with —C(═O)OH;
each R15 is independently selected from H, —CH3 and phenyl;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; and
wherein the antibody fragment that specifically binds to human cKIT is selected from any of the following:
(1) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 (Heavy Chain Complementarity Determining Region 1) comprising the amino acid sequence of SEQ ID NO: 1, (b) a HCDR2 (Heavy Chain Complementarity Determining Region 2) comprising the amino acid sequence of SEQ ID NO: 2, and (c) a HCDR3 (Heavy Chain Complementarity Determining Region 3) comprising the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region that comprises: (d) a LCDR1 (Light Chain Complementarity Determining Region 1) comprising the amino acid sequence of SEQ ID NO: 16, (e) a LCDR2 (Light Chain Complementarity Determining Region 2) comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 (Light Chain Complementarity Determining Region 3) comprising the amino acid sequence of SEQ ID NO: 18;
(2) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 19, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 21;
(3) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18;
(4) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 22, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 18;
(5) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 27, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 28, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43;
(6) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 30, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 31, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 44, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 45;
(7) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 32, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 28, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43;
(8) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 33, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 35; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 46, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 43;
(9) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 60, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 62; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 75, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 76, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 77;
(10) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 63, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 62; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 78, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 79, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 80;
(11) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 65, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 62; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 75, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 76, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 77;
(12) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 66, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 67, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 68; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 81, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 79, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 77;
(13) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 86, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 87, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 88; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 101, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 102, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 103;
(14) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 89, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 90, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 88; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 104, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 106;
(15) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 91, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 87, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 88; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 101, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 102, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 103;
(16) a Fab or Fab′ comprising (i) a heavy chain variable region that comprises (a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 92, (b) a HCDR2 comprising the amino acid sequence of SEQ ID NO: 93, and (c) a HCDR3 comprising the amino acid sequence of SEQ ID NO: 94; and (ii) a light chain variable region that comprises: (d) a LCDR1 comprising the amino acid sequence of SEQ ID NO: 107, (e) a LCDR2 comprising the amino acid sequence of SEQ ID NO: 105, and (f) a LCDR3 comprising the amino acid sequence of SEQ ID NO: 103;
(17) a Fab or Fab′ comprising a heavy chain variable region (VH) that comprises SEQ ID NO: 10, and a light chain variable region (VL) that comprises SEQ ID NO: 23;
(18) a Fab or Fab′ comprising a VH that comprises SEQ ID NO: 36, and a VL that comprises SEQ ID NO: 47;
(19) a Fab or Fab′ comprising a VH that comprises SEQ ID NO: 69, and a VL that comprises SEQ ID NO: 82;
(20) a Fab or Fab′ comprising a VH that comprises SEQ ID NO: 95, and a VL that comprises SEQ ID NO: 108;
(21) a Fab′ comprising a heavy chain that comprises SEQ ID NO: 14, and a light chain that comprises SEQ ID NO: 25;
(22) a Fab′ comprising a heavy chain that comprises SEQ ID NO: 40, and a light chain that comprises SEQ ID NO: 49;
(23) a Fab′ comprising a heavy chain that comprises SEQ ID NO: 73, and a light chain that comprises SEQ ID NO: 84;
(24) a Fab′ comprising a heavy chain that comprises SEQ ID NO: 99, and a light chain that comprises SEQ ID NO:110;
(25) a Fab comprising a heavy chain that comprises SEQ ID NO: 118, and a light chain that comprises SEQ ID NO: 122;
(26) a Fab comprising a heavy chain that comprises SEQ ID NO: 118, and a light chain that comprises SEQ ID NO: 123;
(27) a Fab comprising a heavy chain that comprises SEQ ID NO: 124, and a light chain that comprises SEQ ID NO: 128;
(28) a Fab comprising a heavy chain that comprises SEQ ID NO: 124, and a light chain that comprises SEQ ID NO: 129;
(29) a Fab comprising a heavy chain that comprises SEQ ID NO: 130, and a light chain that comprises SEQ ID NO: 134;
(30) a Fab comprising a heavy chain that comprises SEQ ID NO: 130, and a light chain that comprises SEQ ID NO: 135;
(31) a Fab comprising a heavy chain that comprises SEQ ID NO: 136, and a light chain that comprises SEQ ID NO: 140;
(32) a Fab comprising a heavy chain that comprises SEQ ID NO: 141, and a light chain that comprises SEQ ID NO: 145;
(33) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO: 119, 120 or 121, and a light chain comprising the amino acid sequence of SEQ ID NO: 25;
(34) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO: 125, 126, or 127, and a light chain comprising the amino acid sequence of SEQ ID NO: 49;
(35) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO: 137, 138, or 139, and a light chain comprising the amino acid sequence of SEQ ID NO: 84; or
(36) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO: 142, 143, or 144, and a light chain comprising the amino acid sequence of SEQ ID NO: 110.