US 7,964,566 B2Granted

Monomethylvaline compounds capable of conjugation to ligands

AssigneeSeattle Genetics, Inc.

InventorsSvetlana O. Doronina, Peter D. Senter, Brian E. Toki, Allen J. Ebens, Toni Beth Kline, Paul Polakis, Mark X. Sliwkowski, Susan D. Spencer

Life of this patent

Estimating the term…

Abstract

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

Claims60

Dependent claims

An antibody-drug conjugate compound comprising an antibody covalently attached to one or more drug moieties, the compound having Formula Ic:

Ab Aa-Ww-Yy-D)p Ic
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ab is an antibody which binds to one or more tumor-associated antigens (1)-(35):
(1) BMPR1B (bone morphogenetic protein receptor-type IB;
(2) E16 (LAT1, SLC7A5);
(3) STEAP1 (six transmembrane epithelial antigen of prostate);
(4) 0772P (CA125, MUC16);
(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin);
(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);
(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B);
(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene);
(9) ETBR (Endothelin type B receptor);
(10) MSG783 (RNF124, hypothetical protein FLJ20315);
(11) STEAP2 (HGNC—8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein);
(12) TrpM4 (BR22450, F1120041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4);
(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor);
(14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792);
(15) CD79b (IGb (immunoglobulin-associated beta), B29);
(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C);
(17) HER2;
(18) NCA;
(19) MDP;
(20) IL20Rα;
(21) Brevican;
(22) Ephb2R;
(23) ASLG659;
(24) PSCA;
(25) GEDA;
(26) BAFF-R;
(27) CD22;
(28) CD79a (CD79A, CD79α, immunoglobulin-associated alpha);
(29) CXCR5 (Burkitt's lymphoma receptor 1);
(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+T lymphocytes);
(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5);
(32) CD72 (B-cell differentiation antigen CD72, Lyb-2);
(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family);
(34) FCRH1 (Fc receptor-like protein 1);
and
(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2);
A is a Stretcher unit,
a is 0 or 1,
each W is independently an Amino Acid unit,
w is an integer ranging from 0 to 12,
Y is a Spacer unit, and
y is 0, 1 or 2,
p ranges from 1 to 20, and
D is a drug moiety of Formula DE:
wherein the wavy line of DE indicates the covalent attachment site to A, W, or Y, and independently at each location:
R2 is selected from the group consisting of H and C1-C8 alkyl;
R3 is selected from the group consisting of H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from the group consisting of H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from the group consisting of H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from the group consisting of H and C1-C8 alkyl;
R7 is selected from the group consisting of H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from the group consisting of H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—(C1-C8 alkyl);
R9 is selected from the group consisting of H and C1-C8 alkyl;
and
R18 is selected from the group consisting of —C(R8)2—C(R8)2-aryl, —C(R8)2—C(R8)2—(C3-C8 heterocycle), and —C(R8)2—C(R8)2—(C3-C8 carbocycle).

56 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/833,959Filed 3 Aug 2007 · division
Priority: 6 Nov 2003
Published: US 2008/0248053 A19 Oct 2008
Granted: 21 Jun 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07K 7/02
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: linear peptides containing at least one abnormal peptide link
A61K 47/68031
Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates: the drug being an auristatin
A61K 47/6811
Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates: the drug being a protein or peptide, e.g. transferrin or…
A61K 47/6849
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a receptor, a cell…

Family

Application60/518,534Us provisional application · filed 6 Nov 2003
Application60/557,116Us provisional application · filed 26 Mar 2004
Application60/598,899Us provisional application · filed 4 Aug 2004
Application60/622,455Us provisional application · filed 27 Oct 2004
Application10/983,340Parent of this division · filed 5 Nov 2004
US 2008/0248053 A1Pre-grant publication · published 9 Oct 2008
US 7,498,298 B2Parent of this division
US 2005/0238649 A1Published application
US 7,964,566 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

An antibody-drug conjugate compound comprising an antibody covalently attached to one or more drug moieties, the compound having Formula Ic:

Ab Aa-Ww-Yy-D)p Ic
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ab is an antibody which binds to one or more tumor-associated antigens (1)-(35):
(1) BMPR1B (bone morphogenetic protein receptor-type IB;
(2) E16 (LAT1, SLC7A5);
(3) STEAP1 (six transmembrane epithelial antigen of prostate);
(4) 0772P (CA125, MUC16);
(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin);
(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);
(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B);
(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene);
(9) ETBR (Endothelin type B receptor);
(10) MSG783 (RNF124, hypothetical protein FLJ20315);
(11) STEAP2 (HGNC—8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein);
(12) TrpM4 (BR22450, F1120041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4);
(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor);
(14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792);
(15) CD79b (IGb (immunoglobulin-associated beta), B29);
(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C);
(17) HER2;
(18) NCA;
(19) MDP;
(20) IL20Rα;
(21) Brevican;
(22) Ephb2R;
(23) ASLG659;
(24) PSCA;
(25) GEDA;
(26) BAFF-R;
(27) CD22;
(28) CD79a (CD79A, CD79α, immunoglobulin-associated alpha);
(29) CXCR5 (Burkitt's lymphoma receptor 1);
(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+T lymphocytes);
(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5);
(32) CD72 (B-cell differentiation antigen CD72, Lyb-2);
(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family);
(34) FCRH1 (Fc receptor-like protein 1);
and
(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2);
A is a Stretcher unit,
a is 0 or 1,
each W is independently an Amino Acid unit,
w is an integer ranging from 0 to 12,
Y is a Spacer unit, and
y is 0, 1 or 2,
p ranges from 1 to 20, and
D is a drug moiety of Formula DE:
wherein the wavy line of DE indicates the covalent attachment site to A, W, or Y, and independently at each location:
R2 is selected from the group consisting of H and C1-C8 alkyl;
R3 is selected from the group consisting of H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from the group consisting of H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
R5 is selected from the group consisting of H and methyl;
or R4 and R5 jointly form a carbocyclic ring and have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of H, C1-C8 alkyl and C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R6 is selected from the group consisting of H and C1-C8 alkyl;
R7 is selected from the group consisting of H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from the group consisting of H, OH, C1-C8 alkyl, C3-C8 carbocycle and O—(C1-C8 alkyl);
R9 is selected from the group consisting of H and C1-C8 alkyl;
and
R18 is selected from the group consisting of —C(R8)2—C(R8)2-aryl, —C(R8)2—C(R8)2—(C3-C8 heterocycle), and —C(R8)2—C(R8)2—(C3-C8 carbocycle).

56 more elements

Facts

Application

11/833,959Filed 3 Aug 2007 · division

Priority

6 Nov 2003

Published

US 2008/0248053 A19 Oct 2008

Granted

21 Jun 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07K 7/02
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: linear peptides containing at least one abnormal peptide link
A61K 47/68031
Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates: the drug being an auristatin
A61K 47/6811
Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates: the drug being a protein or peptide, e.g. transferrin or…
A61K 47/6849
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a receptor, a cell…

Family

Application60/518,534Us provisional application · filed 6 Nov 2003

Application60/557,116Us provisional application · filed 26 Mar 2004

Application60/598,899Us provisional application · filed 4 Aug 2004

Application60/622,455Us provisional application · filed 27 Oct 2004

Application10/983,340Parent of this division · filed 5 Nov 2004

US 2008/0248053 A1Pre-grant publication · published 9 Oct 2008

US 7,498,298 B2Parent of this division

US 2005/0238649 A1Published application

US 7,964,566 B2This patent

From the US filing history. Foreign family members aren’t listed.