US2003103985A1PendingUtilityA1
Cytotoxic CD44 antibody immunoconjugates
Est. expiryMay 18, 2021(expired)· nominal 20-yr term from priority
A61K 47/68033A61K 47/6849
51
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Claims
Abstract
The invention relates to novel conjugates of CD44 antibodies with cytotoxic compounds, pharmaceutical compositions comprising such compounds, and their use in tumor therapy.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula (I):
A(LB) n
wherein
A is an antibody molecule which is specific for CD44;
L is a linker moiety;
B is a compound which is toxic to cells; and
n is an decimal number with n=1 to 10.
2 . The compound of claim 1 wherein said linker moiety comprises a chemical bond, wherein said chemical bond is cleavable inside a cell.
3 . The compound of claim 2 wherein said chemical bond is a disulfide bond.
4 . The compound of claims 1 to 3 , wherein the antibody molecule is specific for the exon v6 of human CD44.
5 . The compound of claims 1 to 4 , wherein the antibody molecule is specific for an epitope within the amino acid sequence SEQ ID NO:3.
6 . The compound of claims 1 to 5 , wherein the antibody molecule is the monoclonal antibody VFF-18 (DSM ACC2174) or a recombinant antibody having the complementary determining regions (CDRs) of VFF-18.
7 . The compound of claims 1 to 6 , wherein the antibody molecule comprises light chains having the amino acid sequence SEQ ID NO:4, or SEQ ID NO:8, and heavy chains having the amino acid sequence SEQ ID NO:6.
8 . The compound of claims 1 to 7 , wherein the toxic compound B is a maytansinoid.
9 . The compound of claim 8 wherein the maytansinoid has the formula
wherein
R 1 represents H or SR 4 , wherein R 4 represents methyl, ethyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl, or heterocyclic;
R 2 represents Cl or H;
R 3 represents H or CH 3 ; and
m represents 1, 2, or 3.
10 . The compound of claim 9 , wherein R 1 is H or CH 3 , R 2 is Cl, R 3 is CH 3 , and m=2
11 . The compound of claims 1 to 10 of formula:
wherein
(A) is an antibody molecule which is specific for CD 44
(L′) is an optional linker moiety
p is a decimal number with p=1 to 10.
12 . The compound of claims 1 to 11 wherein p is 3 to 4.
13 . A conjugate of a CD44v6 specific antibody molecule and a maytansinoid.
14 . The conjugate of claim 13 , wherein the antibody molecule is specific for an epitope within the amino acid sequence SEQ ID NO:3.
15 . The conjugate of claim 13 , wherein the antibody molecule is the monoclonal antibody VFF-18 (DSM ACC2174).
16 . The conjugate of claim 13 , wherein the antibody molecule is a recombinant antibody having the complementary determining regions (CDRs) of VFF-18.
17 . The conjugate of claim 13 , wherein the antibody molecule comprises light chains having the amino acid sequence SEQ ID NO:4 or SEQ ID NO:8, and heavy chains having the amino acid sequence SEQ ID NO:6.
18 . The conjugate of any one of claims 13 to 17 , wherein the maytansinoid is linked to the antibody molecule by a disulfide moiety.
19 . A conjugate of a CD44v6 specific antibody molecule and a maytansinoid, wherein the maytansinoid has the formula:
20 . The conjugate of claim 19 , wherein the antibody molecule is specific for an epitope within the amino acid sequence SEQ ID NO:3.
21 . The conjugate of claim 19 , wherein the antibody molecule is the monoclonal antibody VFF-18 (DSM ACC2174).
22 . The conjugate of claim 19 , wherein the antibody molecule is a recombinant antibody having the complementary determining regions (CDRs) of VFF-18.
23 . The conjugate of claim 19 , wherein the antibody molecule comprises light chains having the amino acid sequence SEQ ID NO:4 or SEQ ID NO:8, and heavy chains having the amino acid sequence SEQ ID NO:6.
24 . A conjugate of a CD44v6 specific antibody molecule and a maytansinoid, wherein the antibody comprises light chains having the amino acid sequence SEQ ID NO:4, and heavy chains having the amino acid sequence SEQ ID NO:6, and wherein the maytansinoid has the formula:
and is linked to the antibody through a disulfide bond.
25 . The conjugate of any one of claims 19 to 24 , wherein one or more maytansinoid residues are linked to an antibody molecule.
26 . The conjugate of claim 25 , wherein 3 to 4 maytansinoid residues are linked to an antibody molecule.
27 . The conjugate of any one of claims 19 to 24 , wherein the maytansinoid is linked to the antibody molecule through a —S—CH 2 CH 2 —CO—, a —S—CH 2 CH 2 CH 2 CH 2 —CO—, or a —S—CH(CH 3 )CH 2 CH 2 —CO— group.
28 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 , and a pharmaceutically acceptable carrier, diluent, or excipient.
29 . A pharmaceutical composition comprising a conjugate according to any one of claims 13 to 17 , and a pharmaceutically acceptable carrier, diluent, or excipient.
30 . A pharmaceutical composition comprising a conjugate according to any one of claims 19 to 24 , and a pharmaceutically acceptable carrier, diluent, or excipient.
31 . A method of treatment of cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 12 .
32 . A method of treatment of cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a conjugate according to claims 13 to 17 .
33 . A method of treatment of cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a conjugate according to claims 19 to 24 .
34 . The method of claim 31 , wherein the cancer is selected from the group consisting of:
head and neck squameous cell carcinoma, esophagus squameous cell carcinoma, lung squameous cell carcinoma, skin squameous cell carcinoma, cervix squameous cell carcinoma, breast adenocarcinoma, lung adenocarcinoma, pancreas adenocarcinoma, colon adenocarcinoma, and stomach adenocarcinoma.
35 . The method of claim 32 , wherein the cancer is selected from the group consisting of:
head and neck squameous cell carcinoma, esophagus squameous cell carcinoma, lung squameous cell carcinoma, skin squameous cell carcinoma, cervix squameous cell carcinoma, breast adenocarcinoma, lung adenocarcinoma, pancreas adenocarcinoma, colon adenocarcinoma, and stomach adenocarcinoma
36 . The method of claim 33 , wherein the cancer is selected from the group consisting of:
head and neck squameous cell carcinoma, esophagus squameous cell carcinoma, lung squameous cell carcinoma, skin squameous cell carcinoma, cervix squameous cell carcinoma, breast adenocarcinoma, lung adenocarcinoma, pancreas adenocarcinoma, colon adenocarcinoma, and stomach adenocarcinomaJoin the waitlist — get patent alerts
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