Claims (21)
1. Citotoksični spoj predstavljen slijedećom formulom:
[image]
ili njegova farmaceutski prihvatljiva sol, naznačen time što:
L' je predstavljen sljedećom formulom:
-NR5-P-C(=O)-(CRaRb)m-J (B1);
-NR5-P-C(=O)-Cy-(CRaRb)m'-J (B2);
ili
- NR5-P-C(=O)-( CRaRb)m-S-Zs (B3);
ili pri čemu:
P je aminokiselinski ostatak ili peptid koji sadrži između 2 do 20 aminokiselinskih ostataka;
J je N-hidroksisukcinimid ester, N-hidroksi sulfosukcinimid ester, nitrofenil ester, dinitrofenil ester, sulfo-tetraflurofenil ester i pentafluorofenil ester;
Ra i Rb, za svaku pojavu, su svaki neovisno -H, (C1-C3) alkil ili nabijeni supstituent ili ionizirajuća skupina Q, gdje Q je SO3H ili njegova farmaceutski prihvatljiva sol;
m je cijeli broj od 1 do 6;
m' je 0 ili cijeli broj od 1 do 6;
Cy je ciklički alkil koji ima 5 ili 6 prstenastih atoma ugljika izborno supstituiranih s halogenom, -OH, (C1-C3) alkilom, (C1-C3) alkoksi ili halo (C1-C3) alkilom; i
Zs je -H, -SRd, -C(=O)Rd1 ili je odabran iz bilo koje od sljedećih formula:
[image]
[image]
ili
[image]
naznačen time što:
q je cijeli broj od 1 do 5;
n' je cijeli broj od 2 do 6;
U je -H ili SO3M;
M je H+, Na+ ili K+;
Rd je ravni ili razgranati alkil s 1 do 6 atoma ugljika ili je odabran između fenila, nitrofenila, dinitrofenila, karboksinitrofenila, piridila ili nitropiridila; i
Rd1 je ravni ili razgranati alkil koji ima 1 do 6 atoma ugljika;
L" i L'" su oba -H;
dvostruka linija
[image]
između N i C predstavlja jednostruku ili dvostruku vezu, pod uvjetom da kada je dvostruka veza X odsutna i Y je -H, ili ravni ili razgranati alkil koji ima 1 do 4 atoma ugljika, i kad je jednostruka veza , X je -H, Y je -OH ili -SO3M;
R1, R2, R3, R4, Rl', R2', R3' i R4' su svi -H;
R6 je -OMe;
X 'i Y' su oba -H;
A i A' su -O-; i
M je H, Na+ ili K+; i
R5 je za svaku pojavu neovisno -H ili izborno supstituirani ravni ili razgranati alkil koji ima 1 do 10 atoma ugljika.1. Cytotoxic compound represented by the following formula:
[image]
or its pharmaceutically acceptable salt, characterized in that:
L' is represented by the following formula:
-NR5-P-C(=O)-(CRaRb)m-J (B1);
-NR5-P-C(=O)-Cy-(CRaRb)m'-J (B2);
or
- NR5-P-C(=O)-(CRaRb)m-S-Zs (B3);
or whereby:
P is an amino acid residue or a peptide containing between 2 and 20 amino acid residues;
J is N-hydroxysuccinimide ester, N-hydroxy sulfosuccinimide ester, nitrophenyl ester, dinitrophenyl ester, sulfo-tetrafluorophenyl ester and pentafluorophenyl ester;
Ra and Rb, for each occurrence, are each independently -H, (C1-C3) alkyl or a charged substituent or an ionizable group Q, wherein Q is SO3H or a pharmaceutically acceptable salt thereof;
m is an integer from 1 to 6;
m' is 0 or an integer from 1 to 6;
Cy is cyclic alkyl having 5 or 6 ring carbon atoms optionally substituted with halogen, -OH, (C1-C3) alkyl, (C1-C3) alkoxy or halo (C1-C3) alkyl; and
Zs is -H, -SRd, -C(=O)Rd1 or is selected from any of the following formulas:
[image]
[image]
or
[image]
characterized by:
q is an integer from 1 to 5;
n' is an integer from 2 to 6;
U is -H or SO 3 M;
M is H+, Na+ or K+;
R d is straight or branched alkyl of 1 to 6 carbon atoms or is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl or nitropyridyl; and
Rd 1 is straight or branched alkyl having 1 to 6 carbon atoms;
L" and L'" are both -H;
double line
[image]
between N and C represents a single or double bond, provided that when the double bond X is absent and Y is -H, or straight or branched alkyl having 1 to 4 carbon atoms, and when the single bond is , X is -H, Y is -OH or -SO3M;
R1, R2, R3, R4, R1', R2', R3' and R4' are all -H;
R 6 is -OMe;
X' and Y' are both -H;
A and A' are -O-; and
M is H, Na+ or K+; and
R 5 is for each occurrence independently -H or optionally substituted straight or branched alkyl having 1 to 10 carbon atoms.
2. Spoj prema zahtjevu 1, naznačen time što je L' predstavljen slijedećim formulama:
-NR5-P-C(=O)-(CRaRb)m-J (B1);
ili
- NR5-P-C (=O)-Cy-( CRaRb)m'-J (B2),
izborno gdje su Ra i Rb oba H; Cy za formulu (B2) je cikloheksan; R5 je H ili Me, a m' je 0 ili 1.2. Compound according to claim 1, characterized in that L' is represented by the following formulas:
-NR5-P-C(=O)-(CRaRb)m-J (B1);
or
- NR5-P-C (=O)-Cy-(CRaRb)m'-J (B2),
optionally wherein Ra and Rb are both H; Cy for formula (B2) is cyclohexane; R5 is H or Me and m' is 0 or 1.
3. Spoj prema zahtjevu 2, naznačen time što je L' predstavljen formulom B1.3. Compound according to claim 2, characterized in that L' is represented by formula B1.
4. Spoj prema zahtjevu 1, naznačen time što je L' predstavljen slijedećom formulom:
-NR5-P-C(=O)-(CRaRb)m-S-Zs (B3),
izborno gdje:
(i) Ra i Rb su oba -H, a R5 je H ili Me; ili
(ii) -(CRaRb)m- je -(CH2)m"-C(Me2)- i m" je cijeli broj od 1 do 5.4. Compound according to claim 1, characterized in that L' is represented by the following formula:
-NR5-P-C(=O)-(CRaRb)m-S-Zs (B3),
optional where:
(i) R a and R b are both -H and R 5 is H or Me; or
(ii) -(CRaRb)m- is -(CH2)m"-C(Me2)- and m" is an integer from 1 to 5.
5. Spoj prema bilo kojem od zahtjeva 1-4, naznačen time što P je peptid koji sadrži 2 do 5 aminokiselinskih ostataka.5. A compound according to any one of claims 1-4, characterized in that P is a peptide containing 2 to 5 amino acid residues.
6. Spoj prema zahtjevu 5, naznačen time što je P odabran između Gly-Gly-Gly, Ala-Val, Val-Ala, Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu -Cit, Ile-Cit, Trp-Cit, Phe-Ala, Phe-N9-tozil-Arg, Phe-N9-nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu i Gly-Phe-Leu-Gly, Val-Arg, Arg-Val, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit , D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala -Met i Met-Ala.6. Compound according to claim 5, characterized in that P is selected from Gly-Gly-Gly, Ala-Val, Val-Ala, Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe- Cit, Leu -Cit, Ile-Cit, Trp-Cit, Phe-Ala, Phe-N9-tosyl-Arg, Phe-N9-nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly- Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu and Gly-Phe-Leu-Gly, Val- Arg, Arg-Val, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val- D-Cit , D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D- Ala, Ala-Met and Met-Ala.
7. Spoj prema zahtjevu 1, naznačen time što je spoj izabran iz bilo koje od sljedećih formula:
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
ili
[image]
ili njegova farmaceutski prihvatljiva sol, gdje:
R100 je -OH, -OMe ili
[image] 7. The compound according to claim 1, characterized in that the compound is selected from any of the following formulas:
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
or
[image]
or a pharmaceutically acceptable salt thereof, where:
R 100 is -OH, -OMe or
[image]
8. Spoj prema zahtjevu 7, naznačen time što je spoj predstavljen slijedećim formulama:
[image]
ili
[image]
ili njegova farmaceutski prihvatljiva sol.8. The compound according to claim 7, characterized in that the compound is represented by the following formulas:
[image]
or
[image]
or a pharmaceutically acceptable salt thereof.
9. Konjugat koji sadrži citotoksični spoj i sredstvo za vezanje stanica (CBA), naznačen time što je citotoksični spoj kovalentno povezan sa CBA, i pri čemu je navedeni citotoksični spoj predstavljen slijedećom formulom:
[image]
ili njegova farmaceutski prihvatljiva sol, pri čemu:
sredstvo za vezivanje stanica je antitijelo, antitijelo s jednim lancem, fragment antitijela koje se specifično veže na ciljanu stanicu, monoklonsko antitijelo, jednolančano monoklonsko antitijelo, ili fragment monoklonskog antitijela koje se specifično veže na ciljanu stanicu, himerno antitijelo, fragment himernog antitijela koje se specifično veže na ciljanu stanicu, antitijelo domene, fragment antitijela domene koji se specifično veže na ciljanu stanicu, limfokin, hormon, vitamin, faktor rasta, faktor koji stimulira koloniju, ili molekula transporta hranjivih tvari;
L' je predstavljen slijedećom formulom:
-NR5-P-C(=O)-(CRaRb)m-J' (B1');
-NR5-P-C(=O)-Cy-(CRaRb)m'-J' (B2');
-NR5-P-C(=O)-(CRaRb)m-S-Zs1 (B3');
ili pri čemu:
P je aminokiselinski ostatak ili peptid koji sadrži između 2 do 20 aminokiselinskih ostataka;
J' je -C(=O)- to je kovalentno povezano sa sredstvom za vezanje stanica;
Ra i Rb, za svaku pojavu, su svaki neovisno -H, (C1-C3) alkil ili nabijeni supstituent ili ionizirajuća skupina Q, gdje Q je SO3H ili njegova farmaceutski prihvatljiva sol;
m je cijeli broj od 1 do 6;
m' je 0 ili cijeli broj od 1 do 6;
Cy je ciklički alkil koji ima 5 ili 6 prstenastih atoma ugljika izborno supstituiranih s halogenom, -OH, (C1-C3) alkilom, (C1-C3) alkoksi, ili halo (C1-C3) alkilom;
Zs1 je odabran iz bilo koje od sljedećih formula:
[image]
[image]
i
[image]
gdje:
q je cijeli broj od 1 do 5;
n' je cijeli broj od 2 do 6;
U je -H ili SO3M; i
M je H+, Na+ ili K+;
L" i L'" su oba -H;
dvostruka linija
[image]
između N i C predstavlja jednostruku ili dvostruku vezu, pod uvjetom da kada je dvostruka veza X je odsutan i Y je -H, ili ravni ili razgranati alkil koji ima 1 do 4 atoma ugljika, i kad je jednostruka veza, X je -H, Y je -OH ili -SO3M;
R1, R2, R3, R4, Rl', R2', R3' i R4' su svi -H;
R6 je -OMe;
X' i Y' su oba -H;
A i A' su -O-; i
M je H, Na+ ili K+; i
R5 je za svaku pojavu neovisno -H ili izborno supstituirani ravni ili razgranati alkil koji ima 1 do 10 atoma ugljika.9. A conjugate containing a cytotoxic compound and a cell binding agent (CBA), characterized in that the cytotoxic compound is covalently linked to the CBA, and wherein said cytotoxic compound is represented by the following formula:
[image]
or a pharmaceutically acceptable salt thereof, wherein:
a cell-binding agent is an antibody, a single-chain antibody, an antibody fragment that specifically binds to a target cell, a monoclonal antibody, a single-chain monoclonal antibody, or a fragment of a monoclonal antibody that specifically binds to a target cell, a chimeric antibody, a fragment of a chimeric antibody that specifically binds to a target cell, antibody domain, antibody domain fragment that specifically binds to a target cell, lymphokine, hormone, vitamin, growth factor, colony-stimulating factor, or nutrient transport molecule;
L' is represented by the following formula:
-NR5-P-C(=O)-(CRaRb)m-J' (B1');
-NR5-P-C(=O)-Cy-(CRaRb)m'-J' (B2');
-NR5-P-C(=O)-(CRaRb)m-S-Zs1 (B3');
or whereby:
P is an amino acid residue or a peptide containing between 2 and 20 amino acid residues;
J' is -C(=O)- that is covalently linked to the cell binding agent;
Ra and Rb, for each occurrence, are each independently -H, (C1-C3) alkyl or a charged substituent or an ionizable group Q, wherein Q is SO3H or a pharmaceutically acceptable salt thereof;
m is an integer from 1 to 6;
m' is 0 or an integer from 1 to 6;
Cy is cyclic alkyl having 5 or 6 ring carbon atoms optionally substituted with halogen, -OH, (C1-C3) alkyl, (C1-C3) alkoxy, or halo (C1-C3) alkyl;
Zs1 is selected from any of the following formulas:
[image]
[image]
and
[image]
where:
q is an integer from 1 to 5;
n' is an integer from 2 to 6;
U is -H or SO 3 M; and
M is H+, Na+ or K+;
L" and L'" are both -H;
double line
[image]
between N and C represents a single or double bond, provided that when the double bond is X absent and Y is -H, or straight or branched alkyl having 1 to 4 carbon atoms, and when the single bond is X is -H, Y is -OH or -SO3M;
R1, R2, R3, R4, R1', R2', R3' and R4' are all -H;
R 6 is -OMe;
X' and Y' are both -H;
A and A' are -O-; and
M is H, Na+ or K+; and
R 5 is for each occurrence independently -H or optionally substituted straight or branched alkyl having 1 to 10 carbon atoms.
10. Konjugat prema zahtjevu 9, naznačen time što je L' predstavljen slijedećim formulama:
-NR5-P-C(=O)-(CRaRb)m-J' (B1');
ili
- NR5-P-C(=O)-Cy-(CRaRb)m-J' (B2'),
izborno gdje su Ra i Rb oba H; Cy za formulu B2' je cikloheksan; R5 je H ili Me; a m' je 0 ili 1.10. Conjugate according to claim 9, characterized in that L' is represented by the following formulas:
-NR5-P-C(=O)-(CRaRb)m-J' (B1');
or
- NR5-P-C(=O)-Cy-(CRaRb)m-J' (B2'),
optionally wherein Ra and Rb are both H; Cy for formula B2' is cyclohexane; R 5 is H or Me; and m' is 0 or 1.
11. Konjugat prema zahtjevu 10, naznačen time što je L' predstavljen formulom B1'.11. Conjugate according to claim 10, characterized in that L' is represented by the formula B1'.
12. Konjugat prema zahtjevu 9, naznačen time što je L' predstavljen slijedećom formulom:
-NR5-P-C(=O)-(CRaRb)m-S-Zs1 (B3'),
izborno gdje:
(i) Ra i Rb su oba -H, a R5je H ili Me; ili
(ii) -(CRaRb)m- je - (CH2)m"-C (Me2) - i m" je cijeli broj od 1 do 5.12. Conjugate according to claim 9, characterized in that L' is represented by the following formula:
-NR5-P-C(=O)-(CRaRb)m-S-Zs1 (B3'),
optional where:
(i) R a and R b are both -H and R 5 is H or Me; or
(ii) -(CRaRb)m- is -(CH2)m"-C(Me2)- and m" is an integer from 1 to 5.
13. Konjugat prema bilo kojem od zahtjeva 9-12, naznačen time što je P peptid koji sadrži 2 do 5 aminokiselinskih ostataka.13. Conjugate according to any one of claims 9-12, characterized in that P is a peptide containing 2 to 5 amino acid residues.
14. Konjugat prema zahtjevu 13, naznačen time što je P odabran između Gly-Gly-Gly, Ala-Val, Val-Ala, Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu -Cit, Ile-Cit, Trp-Cit, Phe-Ala, Phe-N9-tozil-Arg, Phe-N9-nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys , Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu, Gly-Phe-Leu-Gly, Val-Arg, Arg -Val, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit , D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala -Met i Met-Ala.14. Conjugate according to claim 13, characterized in that P is selected from Gly-Gly-Gly, Ala-Val, Val-Ala, Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe- Cit, Leu -Cit, Ile-Cit, Trp-Cit, Phe-Ala, Phe-N9-tosyl-Arg, Phe-N9-nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly- Phe-Lys , Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu, Gly-Phe-Leu-Gly, Val- Arg, Arg -Val, Arg-Arg, Val-D-Cyt, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val- D-Cit , D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D- Ala, Ala-Met and Met-Ala.
15. Konjugat prema zahtjevu 9, naznačen time što je spoj izabran iz bilo koje od sljedećih formula:
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
ili
[image]
ili
[image]
ili njegova farmaceutski prihvatljiva sol, pri čemu:
r je cijeli broj od 1 do 10.15. Conjugate according to claim 9, characterized in that the compound is selected from any of the following formulas:
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
or
[image]
or
[image]
or a pharmaceutically acceptable salt thereof, wherein:
r is an integer from 1 to 10.
16. Konjugat prema zahtjevu 15, naznačen time što je konjugat predstavljen slijedećim formulama:
[image]
ili
[image]
ili njegova farmaceutski prihvatljiva sol.16. Conjugate according to claim 15, characterized in that the conjugate is represented by the following formulas:
[image]
or
[image]
or a pharmaceutically acceptable salt thereof.
17. Konjugat prema bilo kojem od zahtjeva 9-16, naznačen time što antitijelo je antitijelo koje ponovno izbija na površinu, jednolančano antitijelo koje ponovno izbija na površinu ili fragment antitijela koje ponovno izbija na površinu; monoklonsko antitijelo, fragment jednolančanog monoklonskog antitijela, ili njihov fragment monoklonskog antitijela; ili humanizirano antitijelo, humanizirano jednolančano antitijelo ili fragment humaniziranog antitijela; i / ili
sredstvo za vezanje stanica je:
(i) antitijelo receptora protiv folata ili njegov fragment antitijela;
(ii) anti-EGFR antitijelo ili njegov fragment antitijela;
(iii) anti-CD33 antitijelo ili njegov fragment antitijela;
(iv) anti-CD19 antitijelo ili njegov fragment antitijela;
(v) anti-Muc1 antitijelo ili njegov fragment antitijela; ili je
(vi) anti-CD37 antitijelo ili njegov fragment antitijela.17. Conjugate according to any one of claims 9-16, characterized in that the antibody is a resurfacing antibody, a resurfacing single-chain antibody or a resurfacing antibody fragment; a monoclonal antibody, a single-chain monoclonal antibody fragment, or a monoclonal antibody fragment thereof; or a humanized antibody, a humanized single-chain antibody, or a fragment of a humanized antibody; and / or
cell binding agent is:
(i) anti-folate receptor antibody or antibody fragment thereof;
(ii) an anti-EGFR antibody or antibody fragment thereof;
(iii) an anti-CD33 antibody or antibody fragment thereof;
(iv) an anti-CD19 antibody or antibody fragment thereof;
(v) an anti-Muc1 antibody or antibody fragment thereof; or is
(vi) an anti-CD37 antibody or antibody fragment thereof.
18. Konjugat prema zahtjevu 17, naznačen time što:
(i) antitijelo receptora protiv folata:
(1) je antitijelo huMOV19;
(2) sadrži:
a) CDR1 teškog lanca SEQ ID NO:1; CDR2 teškog lanca SEQ ID NO:7 i CDR3 teškog lanca SEQ ID NO:3; i
b) CDR1 lakog lanca SEQ ID NO:4; CDR2 lakog lanca SEQ ID NO:5; i CDR3 lakog lanca SEQ ID NO:6; ili
(3) sadrži:
a) varijabilnu regiju teškog lanca (HCVR) koja ima aminokiselinsku sekvencu najmanje oko 90%, 95%, 99% ili 100% identičnu SEQ ID NO:11; i
b) varijabilnu regiju lakog lanca (LCVR) koja ima aminokiselinsku sekvencu najmanje oko 90%, 95%, 99% ili 100% identičnu SEQ ID NO:12 ili SEQ ID NO:13;
(4) sadrži:
a) varijabilnu regiju teškog lanca koja ima aminokiselinsku sekvencu SEQ ID NO:11; i
b) varijabilnu regiju lakog lanca koja ima aminokiselinsku sekvencu SEQ ID NO:12 ili SEQ ID NO:13; ili
(5) sadrži:
a) teški lanac koji ima aminokiselinsku sekvencu SEQ ID NO:8; i
b) laki lanac koji ima aminokiselinsku sekvencu SEQ ID NO:9 ili SEQ ID NO:10;
(ii) anti-EGFR antitijelo:
(1) je huML66 antitijelo;
(2) sadrži:
a) teški lanac koji ima aminokiselinsku sekvencu SEQ ID NO:14; i
b) laki lanac koji ima aminokiselinsku sekvencu SEQ ID NO:15;
(3) je huEGFR-7R; ili
(4) sadrži:
a) teški lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:16; i
b) laki lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:17 ili SEQ ID NO:18;
(iii) anti-CD33 antitijelo:
(1) je huMy9-6 antitijelo; ili
(2) sadrži:
a) imunoglobulinski teški lanac koji ima aminokiselinsku sekvencu SEQ ID NO:23; i
b) laki lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:24;
(iv) anti-CD19 antitijelo:
(1) je huB4 antitijelo; ili
(2) sadrži
a) teški lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:19; i
b) laki lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:20;
(v) anti-Mucl antitijelo:
(1) je huDS6 antitijelo; ili
(2) sadrži:
a) imunoglobulinski teški lanac koji ima aminokiselinsku sekvencu SEQ ID NO:21; i
b) laki lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:22;
(vi) anti-CD37 antitijelo:
(1) je huCD37-3 antitijelo;
(2) sadrži:
a) teški lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:26 ili SEQ ID NO:27; i
b) laki lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:25;
(3) je huCD37-50 antitijelo; ili
(4) sadrži:
a) teški lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:29; i
b) laki lanac imunoglobulina koji ima aminokiselinsku sekvencu SEQ ID NO:28.18. Conjugate according to claim 17, characterized in that:
(i) anti-folate receptor antibody:
(1) is the huMOV19 antibody;
(2) contains:
a) CDR1 of the heavy chain SEQ ID NO:1; CDR2 of the heavy chain of SEQ ID NO:7 and CDR3 of the heavy chain of SEQ ID NO:3; and
b) CDR1 of the light chain SEQ ID NO:4; CDR2 of the light chain SEQ ID NO:5; and CDR3 of the light chain of SEQ ID NO:6; or
(3) contains:
a) a heavy chain variable region (HCVR) having an amino acid sequence at least about 90%, 95%, 99% or 100% identical to SEQ ID NO:11; and
b) a light chain variable region (LCVR) having an amino acid sequence at least about 90%, 95%, 99% or 100% identical to SEQ ID NO:12 or SEQ ID NO:13;
(4) contains:
a) heavy chain variable region having the amino acid sequence of SEQ ID NO:11; and
b) a light chain variable region having the amino acid sequence SEQ ID NO:12 or SEQ ID NO:13; or
(5) contains:
a) heavy chain having the amino acid sequence SEQ ID NO:8; and
b) a light chain having the amino acid sequence SEQ ID NO:9 or SEQ ID NO:10;
(ii) anti-EGFR antibody:
(1) is the huML66 antibody;
(2) contains:
a) heavy chain having the amino acid sequence SEQ ID NO:14; and
b) a light chain having the amino acid sequence SEQ ID NO:15;
(3) is huEGFR-7R; or
(4) contains:
a) immunoglobulin heavy chain having the amino acid sequence SEQ ID NO:16; and
b) immunoglobulin light chain having the amino acid sequence SEQ ID NO:17 or SEQ ID NO:18;
(iii) anti-CD33 antibody:
(1) is the huMy9-6 antibody; or
(2) contains:
a) immunoglobulin heavy chain having the amino acid sequence SEQ ID NO:23; and
b) immunoglobulin light chain having the amino acid sequence SEQ ID NO:24;
(iv) anti-CD19 antibody:
(1) is the huB4 antibody; or
(2) contains
a) immunoglobulin heavy chain having the amino acid sequence SEQ ID NO:19; and
b) immunoglobulin light chain having the amino acid sequence SEQ ID NO:20;
(v) anti-Mucl antibody:
(1) is the huDS6 antibody; or
(2) contains:
a) immunoglobulin heavy chain having the amino acid sequence SEQ ID NO:21; and
b) immunoglobulin light chain having the amino acid sequence SEQ ID NO:22;
(vi) anti-CD37 antibody:
(1) is the huCD37-3 antibody;
(2) contains:
a) immunoglobulin heavy chain having the amino acid sequence SEQ ID NO:26 or SEQ ID NO:27; and
b) immunoglobulin light chain having the amino acid sequence SEQ ID NO:25;
(3) is the huCD37-50 antibody; or
(4) contains:
a) immunoglobulin heavy chain having the amino acid sequence SEQ ID NO:29; and
b) immunoglobulin light chain having the amino acid sequence SEQ ID NO:28.
19. Farmaceutski pripravak, naznačen time što sadrži konjugat prema bilo kojem od zahtjeva 9-18 i farmaceutski prihvatljiv nosač.19. Pharmaceutical preparation, characterized in that it contains a conjugate according to any one of claims 9-18 and a pharmaceutically acceptable carrier.
20. Spoj kako je definirano u bilo kojem od zahtjeva 1-8 ili konjugat definiran u bilo kojem od zahtjeva 9-18 za uporabu kao lijek.20. A compound as defined in any of claims 1-8 or a conjugate defined in any of claims 9-18 for use as a medicament.
21. Spoj kako je definirano u bilo kojem od zahtjeva 1-8 ili konjugat kako je definirano u bilo kojem od zahtjeva 9-18 za uporabu u postupku inhibiranja nenormalnog rasta stanica ili liječenja proliferativnog poremećaja, autoimunog poremećaja, destruktivnog poremećaja kostiju, infektivne bolesti, virusne bolesti, fibrotičke bolesti, neurodegenerativnog poremećaja, bolesti gušterače ili bubrega kod sisavca, koji obuhvaća primjenu navedenom sisavcu terapeutski učinkovite količine spoja ili konjugata i, izborno, kemoterapeutsko sredstvo, izborno gdje:
(i) metoda je za liječenje stanja odabranog iz skupine koja se sastoji od: raka, reumatoidnog artritisa, multiple skleroze, grafta u odnosu na bolest domaćina (GVHD), odbacivanja transplantata, lupusa, miozitisa, infekcije i imunološkog nedostatka;
(ii) metoda je za liječenje raka;
(iii) metoda je za liječenje raka odabranog od raka jajnika, raka gušterače, raka vrata maternice, melanoma, raka pluća (npr., ne-stanični rak pluća), raka dojke, raka pločastih stanica glave i vrata, raka prostate, raka endometrija, limfoma (npr. ne-Hodgkinov limfom), mijelodisplastičnog sindroma (MDS), peritonealnog raka ili leukemije (npr. akutna mijeloidna leukemija (AML), akutna monocitna leukemija, promielocitna leukemija, eozinofilna leukemija, akutna limfobalastična leukemija (npr. B-ALL), kronična limfocitna leukemija (CLL), i kronična mijeloidna leukemija (CML));
(iv) metoda je za liječenje akutne mijeloidne leukemije (AML);
(v) metoda je za liječenje raka jajnika; ili
(vi) metoda je za liječenje ne-staničnog raka pluća.21. A compound as defined in any of claims 1-8 or a conjugate as defined in any of claims 9-18 for use in a method of inhibiting abnormal cell growth or treating a proliferative disorder, an autoimmune disorder, a destructive bone disorder, an infectious disease, viral disease, fibrotic disease, neurodegenerative disorder, pancreatic or kidney disease in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound or conjugate and, optionally, a chemotherapeutic agent, optionally where:
(i) the method is for treating a condition selected from the group consisting of: cancer, rheumatoid arthritis, multiple sclerosis, graft versus host disease (GVHD), transplant rejection, lupus, myositis, infection, and immune deficiency;
(ii) the method is for the treatment of cancer;
(iii) the method is for treating a cancer selected from ovarian cancer, pancreatic cancer, cervical cancer, melanoma, lung cancer (eg, non-small cell lung cancer), breast cancer, head and neck squamous cell cancer, prostate cancer, endometrial cancer , lymphoma (eg non-Hodgkin's lymphoma), myelodysplastic syndrome (MDS), peritoneal cancer or leukemia (eg acute myeloid leukemia (AML), acute monocytic leukemia, promyelocytic leukemia, eosinophilic leukemia, acute lymphoblastic leukemia (eg B-ALL ), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML));
(iv) the method is for the treatment of acute myeloid leukemia (AML);
(v) the method is for the treatment of ovarian cancer; or
(vi) the method is for the treatment of non-cellular lung cancer.