AU2021202063A1 - Cross-linkers and their uses - Google Patents
Cross-linkers and their uses Download PDFInfo
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- AU2021202063A1 AU2021202063A1 AU2021202063A AU2021202063A AU2021202063A1 AU 2021202063 A1 AU2021202063 A1 AU 2021202063A1 AU 2021202063 A AU2021202063 A AU 2021202063A AU 2021202063 A AU2021202063 A AU 2021202063A AU 2021202063 A1 AU2021202063 A1 AU 2021202063A1
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- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
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- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
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- RSIXESLSSCMBFT-UHFFFAOYSA-N trimethyl-(2-oxothiolan-3-yl)azanium Chemical compound C[N+](C)(C)C1CCSC1=O RSIXESLSSCMBFT-UHFFFAOYSA-N 0.000 description 1
- DXNOXZQLCKOBFT-UHFFFAOYSA-M trimethyl-(2-oxothiolan-3-yl)azanium;acetate Chemical compound CC([O-])=O.C[N+](C)(C)C1CCSC1=O DXNOXZQLCKOBFT-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
CROSS-LINKERS AND THEIR USES
Abstract
Charged or pro-charged cross-linking moieties and conjugates of cell binding agents and drugs
comprising the charged or pro-charged cross-linking moieties and method of making the same.
Description
[01] The present invention relates to the synthesis of novel charged
cross linkers and cross linkers which can be processed by a target cell to give
charged moieties. The present invention also relates to methods of making
cell-binding agent-drug conjugates comprising modification of cell-binding
agents with these cross-linkers, followed by reaction with drugs, or
modification of the drugs with these crosslinkers, followed by reaction with
cell-binding agents. The improved method of making conjugates provides the
ability to link a higher number of drug molecules per cell-binding agent
resulting in greater potency and providing greater aqueous solubility to the
conjugates.
[02] The bifunctional modification reagent N-succinimidyl 3-(2
pyridyldithio) propionate (SPDP) has been used to link two proteins together
through a disulfide bond. The reagent is reacted with the first protein to
introduce an active disulfide-containing group in the modification step. A
second protein, which contains a free thiol group, is then added to form a disulfide bond between the two proteins in the conjugation step. Many derivatives of SPDP and imide versions of SPDP have been described (U.S.
Patent 4,563,304; J. Carlsson et al. 173 Biochem. J. 723-737 (1978); Goff D.
A., Carroll, S. F. 1 BioConjugate Chem. 381-386 (1990); L. Delprino et al. 82
J Pharm. Sci. 506-512 (1993); S. Arpicco et al., 8 BioConjugate Chem
327-337 (1997)).
[031 Conjugates of cell-binding agents with highly cytotoxic drugs
have been described (U.S. Patent Nos. 5,208,020, 5,416,064; 5,475,092,
5,585,499, 6,436,931, 6,372,738 and 6,340,701; R.V.J. Chari et al., 52 Cancer
Res. 127-131 (1992)). In these conjugates, the cell-binding agents are first
modified with a bifunctional agent such as SPDP, SPP or SMCC to introduce
an active disulfide or a maleimido moiety. Reaction with a thiol-containing
cytotoxic drug provides a conjugate in which the cell-binding agent, such as a
monoclonal antibody, and drug are linked via disulfide bonds or thioether
bonds.
[041 Heterobifunctional cross-linkers comprising a
nitropyridyldithio, dinitropyridyldithio, N.N-dialkylcarboxamidopyridyldithio
or di-(N.N-dialkylcarboxamido) pyridyldithio group and a reactive carboxylic
ester group such as a N-succinimidyl ester group or a N-sulfosuccinimidyl
ester group have been described (U.S. Patent No. 6,913,748). The presence of
a N-sulfosuccinimidyl group was claimed to provide higher aqueous solubility
to these cross-linkers. However, once the cell-binding agent has been reacted with these cross-linkers, the N-sulfosuccinimidyl group is displaced and the solubility advantage is lost, both for the modified cell-binding agent and its drug conjugate. Since cytotoxic drugs used in cell-binding agent-drug conjugates are often only sparingly soluble in aqueous solutions, it is often difficult to link a sufficient number of drug molecules to the cell-binding agent and still maintain aqueous solubility. In addition, reactions have to be conducted in dilute solutions, which are cumbersome to scale up because of the need to use large volumes of solution.
[05] The present invention provides charged linkers, wherein the
charges are retained both after modification of the cell-binding agent and in
the resulting drug conjugate. More specifically, the present invention relates
to the use of charged linkers to link drugs to a cell-binding agent (e.g., an
antibody). In one aspect of the invention, the charged linkers are used to
modify cell-binding agents and link them to drugs. In another aspect of the
invention, the charged linkers are used to modify drugs and link them to cell
binding agents. In yet another aspect of the invention, the charged linkers are
used to simultaneously link drugs and the cell-binding agents. In all instances,
the preferred end result is a drug-charged linker-cell-binding agent conjugate,
which can be represented by the formula, CB-(-Lc-D)q, wherein CB is a cell
binding agent, Lc is a charged linker, D is a drug molecule, and q is an integer
from 1 to 20. The presence of a charged group(s) in the linker in the cell binding agent-drug conjugate provides several advantages, such as i) greater water solubility of the final product, ii) ability to operate at a higher concentration in aqueous solutions, iii) ability to link a greater number of drug molecules per molecule of cell-binding agent, resulting in higher potency, iv) potential for the charged conjugate species to be retained inside the target cell, resulting in higher potency, and v) improved sensitivity of multidrug resistant cells, which would be unable to export the charged drug species from the cell.
The invention also describes linkers, which can be coupled to a drug and a cell
binding agent to give a conjugate which can be metabolized in a cell to
produce a drug metabolite containing one or more charged moieties. These
linkers will be referred to as pro-charged linkers. Moieties of the linker which
will become charged after cell processing will be referred to as pro-charged
moieties.
[06] In one aspect of the present invention, the charged or pro
charged cross linker is represented by formula (I) wherein Y' can react with a
cell-binding agent and Q can react with a cytotoxic drug:
R7 R 8 R3 Y' Z Q
R9 RIO R5 R6 R 1 R2
wherein:
Y' represents a functional group that enables reaction with a
cell-binding agent;
Q represents a functional group that enables linkage of a
cytotoxic drug via a disulfide, thioether, thioester, peptide, hydrazone, ether,
ester, carbamate or amide bond;
R 1, R2, R3, R4 , R 5, R6, R7, R 8, R9, and RIO are the same or
different and are H, linear alkyl having from 1-6 carbon atoms, branched or
cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic
alkenyl or alkynyl having from 2 to 6 carbon atoms, anions, such as but not
2 2 , P0 2 , X-P 2-, CO2, and cations, limited to, S0 3 ~, X-S0 3 ~, OP0 3 -, X-OP0 3 3 3
such as but not limited to, a nitrogen containing heterocycle, N+RuR 12R1 3 or
X-N*R 1 R 12 R, or a phenyl, wherein:
R 1 1, R12 and R 13 are the same or different and are H, linear
alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having
from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl having
from 1 to 6 carbon atoms, or a branched or cyclic alkyl having from 3 to 6
carbon atoms;
1, m and n are 0 or an integer from 1 to 4; and
A is a phenyl or a substituted phenyl, wherein the substituent is
a linear alkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl
having from 3 to 6 carbon atoms, or a charged substituent selected from
anions, such as but not limited to, S0 3 ~, X-SO3~, OP 2, X-OP 3 2 -, P0 3 2 , X
P0 3 2-, C02~, and cations, such as but not limited to, a nitrogen containing
heterocycle, N*R 1iR 12 R 13 or X-N*Ri 1 R 12 R 31, wherein X has the same
definition as above, and wherein g is 0 or 1;
Z is an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p,
wherein p is 0 or an integer from 2 to about 1000, or F1-E1-P-E2-F2 unit in
which El and E2 are the same or different and are C=,0, or NR 14 , wherein
R 14 is H, a linear alkyl having from 1-6 carbon atoms, a branched or cyclic
alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or
alkynyl having from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20
amino acids in length, wherein El or E2 can be linked to the peptide through
the terminal nitrogen, terminal carbon or through a side chain of one of the
amino acids of the peptide; and F1 and F2 are the same or different and are an
optional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, wherein p is 0 or an
integer from 2 to about 1000, provided that when Z is not F1-El-P-E2-F2, at
least one of R1 , R2 , R3 , R 4 , R5 , R 6 , R7 , R8 , R9 , and RIO is a charged substituent
5 , R 6, R 7, R8 , R9 , and RIO is a 1 , R 2, R3, R 4, R or when g is 1, at least one of A, R
charged substituent.
[07] In another aspect, the present invention provides a cell-binding
agent-drug conjugate of formula (II), in which the cell-binding agent, CB, and
the drug, D, have reacted at the two ends of the charged or pro-charged cross
linker:
R7 R 8 R3 R4 Y D CB Ag n _ R9 RIO R5R6 R, R2 _ q
wherein:
CB represents a cell-binding agent;
D represents the drug linked to the cell-binding agent by a disulfide,
thioether, thioester, peptide, hydrazone, ether, ester, carbamate, or amide
bond;
R 1, R2, R3, R 4, R 5, R6, R7, R 8, R9, and RIO are the same or different and
are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl
having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl
having from 2 to 6 carbon atoms, anions, such as but not limited to, S0 3 ~. X
2 2 S0 3 ~. OP0 3 ~, X-OPO3 2-, P0 3 -, X-P0 32-, C0 2 ~, cations, such as but limited to,
a nitrogen containing heterocycle, NRIR12R3 or X-N*RIiR 12 RI 3 , or a
phenyl, wherein:
R, R1 2 and R13 are the same or different and are H, linear
alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3
to 6 carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6
carbon atoms, or a branched or cyclic alkyl having from 3 to 6 carbon atoms;
1, m and n are 0 or an integer from 1 to 4; and
A is a phenyl or substituted phenyl, wherein the substituent is a
linear alkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl
having from 3 to 6 carbon atoms, or a charged substituent selected from
anions, such as but not limited to, S03~. X-S0 3 ~. OP0 32-, X-OP0 32-, PO 32-5 X
P0 3 -, C0 2 -, cations, such as but not limited to, a nitrogen containing
heterocycle, N*R1 1R 12 R13 or X-N+R 1 1R 12 R 31, wherein X has the same
definition as above, and wherein g is 0 or 1;
Z is an optional polyethyleneoxy unit of formula (OCH2 CH2 )p,
wherein p is 0 or an integer from 2 to about 1000, or F1-E1-P-E2-F2 unit in
which El and E2 are the same or different and are C=O,0, or NR14, wherein
R 14 is H, a linear alkyl having from 1-6 carbon atoms, a branched or cyclic
alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or
alkynyl having from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20
amino acids in length, wherein El or E2 can be linked to the peptide through
the terminal nitrogen, terminal carbon or through a side chain of one of the
amino acids of the peptide; and F1 and F2 are the same or different and are an
optional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, wherein p is 0 or an
integer from 2 to about 1000, provided that when Z is not F1-El-P-E2-F2, at
least one of R1 , R2, R3, R 4, R5 , R6 , R7, R8 , R9 , and RIO is a charged substituent
5 , R 6 , R 7, R8 , R 9, and RIO is a 1 , R 2, R 3, R 4 , R or when g is 1, at least one of A, R
charged substituent;
Y represents a carbonyl, thioether, amide, disulfide, or
hydrazone group; and q represents an integer from 1 to 20.
[08] In a further aspect, the present invention provides a modified
cell-binding agent of formula (III), in which the cell-binding agent, CB, has
reacted with the cross linker, which still has Q, a group capable of reacting
with a cytotoxic drug:
R7 R R3 R ~ -Y Zs C 1A
. R9 Rio R5R6 Ag R2_ q
wherein the substituents are as defined above.
[09] In an even further aspect, the present invention provides a
modified drug of formula (IV), in which the drug, D, has reacted with the
cross linker, which still has Y', a group capable of reacting with the cell
binding agent:
R7 R8 R3 R4 Y1 D 1Ag nI m R9 RIO R 5 R 6 R1 R2
wherein the substituents are as defined above.
[10] The present invention further relates to a method of making a
cell-binding agent drug conjugate of formula (II), wherein the drug is linked to
a cell-binding agent via a charged or pro-charged linker.
[11] The present invention also relates to a method of making a
modified cell-binding agent of formula (III), wherein the cell-binding agent is
reacted with the charged or pro-charged linker.
[12] The present invention also relates to a method of making a
modified drug of formula (IV), wherein the drug is reacted with the charged or
pro-charged linker.
[13] The present invention includes a composition (e.g., a
pharmaceutical composition) comprising conjugates or derivatives thereof
(and/or solvates, hydrates and/or salts thereof) and a carrier (a
pharmaceutically acceptable carrier). The present invention also includes a
composition (e.g., a pharmaceutical composition) comprising conjugates or
derivatives thereof, (and/or solvates, hydrates and/or salts thereof) and a
carrier (a pharmaceutically acceptable carrier), further comprising a second therapeutic agent. The present compositions are useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal (e.g., human).
[14] The present invention includes a method of inhibiting abnormal
cell growth or treating a proliferative disorder in a mammal (e.g., human)
comprising administering to said mammal a therapeutically effective amount
of the conjugates or derivatives thereof, (and/or solvates and salts thereof) or a
composition thereof, alone or in combination with a second therapeutic agent.
[15] The compounds of this invention, derivatives thereof, or
conjugates thereof, and compositions comprising them, are useful for treating
or lessening the severity of disorders, such as, characterized by abnormal
growth of cells (e.g., cancer). Other applications for compounds or conjugates
of this invention include, but are not limited to, treating osteoporosis,
depression, anxiety, stress, phobias, panic, dysphoria, psychiatric disorders,
and pain or as antiepileptics, antibacterials, diuretics and hypotensives,
hypolipidemics, and anti-depressants.
[161 Figure 1 shows the synthesis of sulfonic acid-containing cross
linking reagents that contain a nitropyridyldisulfide group and a reactive
carboxylic acid ester. Hydroxyalkanoate esters are first converted into dibromoalkanoate esters as shown, followed by conversion of the a-bromo substituent into a sulfonic acid.
[17] Figure 2 shows the synthesis of sulfonic acid-containing cross
linking reagents that contain a pyridyldisulfide group and a reactive carboxylic
acid ester.
[181 Figures 3, 4 and 5 show various routes for the synthesis of
charged cross-linking agents bearing a reactive carboxylic acid ester and
maleimido substituent, enabling linkage via thioether bonds.
[19] Figures 6 and 7 show the synthesis of phosphate-containing
cross-linking reagents that contain a pyridyldisulfide group and a reactive
carboxylic acid ester.
[20] Figure 8 shows the synthesis of phosphate-containing cross
linking reagents that contain a nitropyridyldisulfide group and a reactive
carboxylic acid ester
[21] Figures 9 and 10 show different routes for the synthesis of
phosphate-containing charged cross-linking agents bearing a reactive
carboxylic acid ester and a maleimido substituent, enabling linkage via
thioether bonds.
[22] Figure 11 shows the synthesis of sulfonic acid-containing
cross-linking reagents, where the sulfonate substituent is attached to a
branched alkyl group. These reagents also bear a pyridyldisulfide group and a
reactive carboxylic acid ester.
[231 Figure 12 shows the synthesis of sulfonic acid-containing
cross-linking reagents, where the sulfonate substituent is attached to a
branched alkyl group. These reagents also bear a reactive carboxylic acid
ester and a maleimido group that allows for linkage via thioether bonds.
[241 Figure 13 shows the synthesis of quartenary amine-containing
cross-linking reagents that contain a pyridyldisulfide group and a reactive
carboxylic acid ester.
[25] Figure 14 shows the synthesis of quartenary amine cross
linking agents bearing a reactive carboxylic acid ester and maleimido
substituent, enabling linkage via thioether bonds.
[26] Figure 15 shows the synthesis of sulfonic acid-containing
cross-linking reagents that contain a pyridyldisulfide group and a reactive
carboxylic acid ester. In these compounds, the sulfonate substituent is on the
carbon atom on the position P to the carboxyl ester.
[27] Figure 16 shows the synthesis of phosphate-containing cross
linking reagents that contain a pyridyldisulfide group and a reactive carboxylic
acid ester. In these compounds, the phosphate substituent is on the p-position
relative to the carboxyl ester.
[28] Figures 17, 18 and 19 show the synthesis of various sulfonic
acid-containing cross-linking reagents that contain a polyethyleneglycol
(PEG) chain, along with a nitropyridyldisulfide group and a reactive
carboxylic acid ester.
[29] Figures 20 and 21 show the synthesis of various sulfonic acid
containing cross-linking reagents that contain a polyethyleneglycol (PEG)
chain, along with a maleimido group and a reactive carboxylic acid ester.
[30] Figure 22 shows the synthesis of phosphate-containing cross
linking reagents, where the phosphate substituent is attached to an aromatic
group. These reagents also bear a reactive carboxylic acid ester and a
nitropyridyldithio group that allows for linkage via disulfide bonds.
[31] Figure 23 shows the synthesis of phosphate-containing cross
linking reagents, where the phosphate substituent is attached to a branched
alkyl group. These reagents also bear a reactive carboxylic acid ester and a
nitropyridyldithio group that allows for linkage via disulfide bonds.
[32] Figures 24 - 31 show the synthesis of sulfonate-containing
cross-linking reagents that also incorporate a hydrazide moiety allowing for
linkage via acid-labile bonds.
[33] Figures 32 - 36 show the synthesis of phosphate-containing
cross-linking reagents that also incorporate a hydrazide moiety allowing for
linkage via acid-labile bonds.
[34] Figures 37 - 38 show the synthesis of quartenary amine
containing cross-linking reagents that also incorporate a hydrazide moiety
allowing for linkage via acid-labile bonds.
[35] Figures 39 - 42 show the synthesis of charged cross-linking
reagents that also incorporate a polyethyleneglycol (PEG) moiety.
[361 Figures 43-44 show the synthesis of phosphate-containing
cross-linking reagents, where the phosphate substituent is attached to an
aromatic residue or to an alkyl group. These reagents also bear a reactive
carboxylic acid ester and a nitropyridyldithio group that allows for linkage via
disulfide bonds.
[37] Figures 45-49 show the synthesis of charged cross-linking
agents bearing reactive carboxylic acid ester and a haloacetyl substituent,
enabling linkage via thioether bonds.
[38] Figure 50 shows the synthesis of a procharged linker that would
generate a negatively charged carboxylate metabolite.
[39] Figure 51 shows a conjugate of linker 158 to a drug and a
monoclonal antibody and how the conjugate would be processed in the
lysosome of a target cell to give a metabolite containing the drug bearing a
negatively charged carboxylate.
[401 Figure 52 shows the synthesis of a procharged linker that would
generate a positively charged amine-containing metabolite.
[41] Figure 53 shows a conjugate of a procharged linker to a drug
and a monoclonal antibody and how the conjugate would be processed in the
lysosome of a target cell to give a metabolite of the drug bearing a positively
charged amine.
[42] Figure 54 shows the synthesis of a procharged linker that would
generate a charged carboxylate metabolite.
[43] Figure 55 shows a conjugate of linker 172 to a drug and a
moloclonal antibody and how the conjugate would be processed in the
lysosome of a target cell to give a metabolite containing the drug bearing a
carboxylic acid and a lysine residue.
[441 Figure 56 shows the use of charged linker in modifying a cell
binding agent and producing a cell-binding agent-drug conjugate bearing a
charged linker.
[451 Figures 57(A), (B) and (C) show the in vitro potency of cell
binding agent-drug conjugates in which a charged crosslinker is incorporated.
[46] Figure 58 shows the in vitro potency and target selectivity of
cell-binding agent-drug conjugates bearing a charged crosslinker.
[47] Figure 59 shows the mass spectrum of cell-binding agent-drug
conjugates bearing a charged crosslinker.
[48] Figure 60 shows the cytotoxicity of Anti-CanAg (huC242)
sulfonate linker-maytansinoid conjugates with increasing maytansinoids load
(E:A) toward COL0205 cells.
[491 Figure 61 shows the cytotoxicity of Anti-CanAg (huC242)
sulfonate linker-maytansinoid conjugates with increasing maytansinoids load
(E:A) toward multi-drug resistant COL0205-MDR cells.
[50] Figure 62 compares cytotoxicity of Anti-CanAg (huC242)
maytansinoid conjugates with or without sulfonate group in the linker toward
multi-drug resistant COL0205-MDR cells.
[51] Figure 63 compares the cytotoxicity of Anti-EpCAM (B38.1)
maytansinoid conjugates with or without sulfonate group in linker toward
multi-drug resistant COL0205-MDR cells.
[52] Figure 64 compares the cytotoxicity of Anti-EpCAM (B38.1)
maytansinoid conjugates with or without sulfonate group in linker toward
multi-drug resistant HCT15 cells.
[53] Figure 65 compares the cytotoxicity of Anti-EpCAM (B38.1)
maytansinoid conjugates with or without sulfonate group in linker toward
multi-drug resistant COL0205-MDR cells.
[54] Figure 66 shows the in vivo anti-tumor activity of anti-EpCAM
antibody-maytansinoid conjugates on COL0205 mdr xenografts (individual
tumors).
[55] Figure 67 shows the in vivo anti-tumor activity of anti-EpCAM
antibody-maytansinoid conjugates on COL0205 xenografts (individual
tumors).
[56] Figures 68 - 70 show the methods of synthesis of sulfonic acid
containing cross-linking reagents. These reagents bear a reactive carboxylic
acid ester and a maleimido group that allows for linkage via thioether bonds.
[57] Figure 71 shows the methods of synthesis of quartenary amine
containing cross-linking reagents. These reagents also bear a reactive
carboxylic acid ester and a pyridyldithio group that allows for linkage via
disulfide bonds.
[58] Figures 72(A) and (B) show Plasma pharmacokinetics of
huC242 Antibody-Sulfo-Mal- [3H-labeled]-DM4 conjugates with 3.5 DM4/Ab
or 6.4 DM4/Ab dosed at 12.9 mg/kg and 7.9 mg/kg (i.v.) respectively in CD-1
mice. A. Ab concentrations (measured by ELISA or by 3H counts) versus
time after administration. B. Maytansinoid (DM4)/Antibody (Ab) ratio
versus time after administration.
[59] In Figures 1-71, where applicable, n reperesents 0 or an integer
from 1 to 10, and m represents 0 or an integer from 1 to 2000.
[60] The novel conjugates disclosed herein use charged or pro
charged cross-linkers. Examples of some suitable cross-linkers and their
synthesis are shown in Figures 1 to 10. Preferably, the charged or pro-charged
cross-linkers are those containing sulfonate, phosphate, carboxyl or quaternary
amine substituents that significantly increase the solubility of the modified
cell-binding agent and the cell-binding agent-drug conjugates, especially for
monoclonal antibody-drug conjugates with 2 to 20 drugs/antibody linked.
Conjugates prepared from linkers containing a pro-charged moiety would produce one or more charged moieties after the conjugate is metabolized in a cell.
Cross-linkers
[61] The synthetic routes to produce charged crosslinkers of the
present invention are shown in Figures 1-49. Synthetic routes to produce
linkers with pro-charged moieties are shown in figures 50, 52, and 54. Figures
51, 53 and 55 show a conjugate of each of the respective pro-charged linkers
with a drug and a monoclonal antibody and how these conjugates would be
metabolized in a target cell to give charged metabolites. The crosslinkers
possess three elements: a) a substituent that is either charged or will become
charged when conjugates employing these linkers are metabolized in cells.
The charge will be either anionic, such as but not limited to, carboxylate,
sulfonate or phosphate, or cationic, such as but not limited to, a tertiary,
quaternary, or primary amine or a nitrogen-containing heterocycle, b) a group,
such as a N-hydroxysuccimimide ester, maleimido group, haloacetyl group,
and hydrazide, capable of reaction with a cell-binding agent, and c) a group,
such as but not limited to, a disulfide, maleimide, haloacetyl, and hydrazide,
capable of reaction with a drug. The charged or pro-charged substituent can
be introduced by methods described herein. For example, a sulfonate charge
can be introduced by first treating a commercially available haloester
compound with thioacetate to produce a thioacetyl compound, followed by
oxidation of the thioacetyl group, using hydrogen peroxide, to a sulfonate group. Phosphate containing crosslinkers can be synthesized by methods described herein. First the desired reactive group, such as but not limited to, thiol, maleimide, haloacetyl and hydrazide, is introduced by the reactions shown in Figures 6-10, followed by hydrolysis of the phosphate ester to give the charged crosslinker bearing a phosphate. A positively charged quaternary amine substituent can be introduced in the crosslinker by reaction of an amine with an a,p-unsaturated ketone (see, for example, Figures 13 and 37).
Alternatively a charged amine substituent can be introduced by displacement
of a halogen with the amine or nitrogen containing heterocycle of choice.
[621 Preferably, the cross-linkers are compounds of the formula (I)
below:
R7 R 8 R3 R4
1 -Ag n R9 RIO R 5 R6 R, R2
wherein Y' represents a functional group that enables reaction
with a cell-binding agent;
Q represents a functional group that enables linkage of a drug via a disulfide, thioether , thioester, peptide, hydrazone, ester, ether, carbamate
or amide bond;
R 1, R2 , R3 , R4 , R5 , R 6, R7, R 8, R9 , and Rio are the same or
different and are H, linear alkyl having from 1-6 carbon atoms, branched or
cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic
alkenyl or alkynyl having from 2 to 6 carbon atoms, anions, such as but not 2 2 limited to, S0 3 ~, X-S0 3-, OP0 32-, X-OPO3 2 ~, P0 3 , X-P0 3 , C0 2-, cations,
such as but not limited to, a nitrogen containing heterocycle, N+R 1 R1 2 R1 3 or
X-N+R 1 R 12R 13 or a phenyl, wherein:
R 1 , RI2 and R 13 are the same or different and are H, linear
alkyl having from 1 to 6 carbon atoms, or branched or cyclic alkyl having
from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl having
from 1 to 6 carbon atoms, or a branched or cyclic alkyl having from 3 to 6
carbon atoms;
1, m and n are 0 or an integer from 1 to 4;
A is a phenyl or substituted phenyl, wherein the substituent is a
linear alkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl
having from 3 to 6 carbon atoms, or a charged substituent selected from
anions, such as but not limited to, S03 ~. X-SO3-. OP0 2 3 , X-OP 3 2 , PO 3 2 , X
P0 3 2 ~, C0 2 -, and cations, such as but not limited to, a nitrogen containing
heterocycle, N*RR 12 R 13 or X-N*R 1 R 12 RI 3 , wherein X has the same
definition as above, and wherein g is 0 or 1;
Z is an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p,
wherein p is 0 or an integer from 2 to about 1000, or F1-E1-P-E2-F2 unit in which El and E2 are the same or different and are C=O,0, or NR14, wherein
R 14 is H, a linear alkyl having from 1-6 carbon atoms, a branched or cyclic
alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or
alkynyl having from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20
amino acids in length, wherein El or E2 can be linked to the peptide through
the terminal nitrogen, terminal carbon or through a side chain of one of the
amino acids of the peptide; and Fl and F2 are the same or different and are an
optional polyethyleneoxy unit of formula (OCH2 CH 2 )p, wherein p is 0 or an
integer from 2 to about 1000, provided that when Z is not F1-E1-P-E2-F2, at
least one of R1 , R2 , R3 , R4 , R5 , R 6, R 7, R8 , R9 , and Rio is a charged substituent
or when g is 1, at least one of A, RI, R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , and Rio is a
charged substituent.
[63] Examples of the functional group, Y', that enables reaction
with a cell-binding agent include amine reacting agents such as but not limited
to N-hydroxysuccinmide esters, p-nitrophenyl esters, dinitrophenyl esters,
pentafluorophenyl esters; thiol reactive agents such as but not limited to
pyridyldisulfides, nitropyridyldisulfides, maleimides, haloacetates and
carboxylic acid chlorides.
[64] Examples of the functional group, Q, which enables linkage of
a cytotoxic drug, include groups that enable linkage via a disulfide, thioether,
thioester, peptide, hydrazone, ester, carbamate, or amide bond. Such functional groups include, but are not limited to, thiol, disulfide, amino, carboxy, aldehydes, maleimido, haloacetyl, hydrazines, and hydroxy.
[651 Examples of linear alkyls include methyl, ethyl, propyl, butyl,
pentyl and hexyl. Examples of branched or cyclic alkyls having 3 to 6 carbon
atoms include isopropyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[66] Examples of linear alkenyls having 2 to 6 carbon atoms
include ethenyl, propenyl, butenyl, pentenyl, hexenyl. Examples of branched
or cyclic alkenyls having 2 to 6 carbon atoms include isobutenyl, isopentenyl,
2-methyl-I-pentenyl, 2-methyl-2-pentenyl.
[67] Examples of linear alkynyls having 2 to 6 carbon atoms include
ethynyl, propynyl, butynyl, pentynyl, hexynyl. Examples of branched or
cyclic alkynyls having up to 6 carbon atoms include 3-methyl-1-butynyl, 3
methyl-I-penynyl, 4-methyl-2-hexynyl.
[68] In preferred embodiments, one of R 1, R2 , R3 , R4, R9 , RIO is a
charged substituent selected from sulfonate, phosphate or trialkylammonium,
and the rest are H, 1, g and m are each 0, n = 1, Q and Y' are each
independently, a disulfide substituent, a maleimido, a haloacetyl group, or a
N-hydroxy succinimide ester. In another more preferred embodiment, one of
R 1, R2, R3, R 4, R9, Rio is a sulfonate, and the rest are H, 1, g and m are each 0,
n = 1, Q is a disulfide, maleimido or haloacetyl moiety, and Y' is a maleimido
moiety or a N-hydroxy succinimide ester. In a further more preferred embodiment, one of R 1, R2, R3, R4 , R9 , Rio is a sulfonate, and the rest are H, 1, g and m are each 0, n = 1, Q is a pyridyldithio or nitropyridyldithio group, maleimido or haloacetyl moiety, and Y' is a N-hydroxy succinimide ester.
[69] The synthesis of 2-dithionitropyridyl and 2-dithio
dinitropyridyl containing cross-linkers of formulae (I) is shown, for example,
in Figures 1, 2 and the synthesis of the corresponding 4-dithionitropyridyl and
4-dithio-dinitropyridyl containing cross-linkers of the formula (I) is shown, for
example, in Figure 6. The synthesis of maleimido-containing charged cross
linkers of the formula (I) with a sulfonate group is shown, for example, in
Figures 3, 4 and 5. The synthesis of maleimido-containing charged cross
linkers of the formula (I) with a phosphate group is shown, for example, in
Figures 9 and 10. The synthesis of quaternary amine-containing charged
crosslinkers of formula (I) is shown, for example, in Figures 13 and 14. The
synthesis of polyethylene glycol-containing charged cross linkers of formula
(I) are shown, for example, in Figures 17 -21. The synthesis of charged cross
linkers of formula (I) bearing a hydrazide moiety enabling linkage via acid
labile bonds is shown, for example, in Figures 24-36.
Cell-binding agent drug -conjugates
[70] Using the charged or pro-charged crosslinkers a high number
(>6) of drug molecules can be introduced. In non limiting examples, Figure
57 exemplifies that cell-binding agent-drug conjugates prepared using a
charged crosslinker of the present invention display high potency. In addition, the potency is target selective (see, for example, Figure 58), since, even after linkage of a high number of drug molecules, the conjugate is highly potent towards target cells, but much less potent towards non-target cells. As exemplified in Figure 59, mass spectral analysis demonstrates that the drugs are linked covalently to the cell-binding agent via the charged crosslinker.
[711 The conjugates of the present invention can be represented by
the following formula, CB-(-L°-D), wherein CB is a cell-binding agent, L' is
a charged or pro-charged linker, D is a drug molecule, and q is an integer from
1 to 20.
[72] Preferably, the conjugates have the following formula (II):
R7 P8 R3 R4 Y ZD CB-W
R9 R10 R5 R6 In Ag R n R2 j q
wherein CB represents a cell-binding agent,
D represents a drug linked to the cell-binding agent by a
disulfide, thioether, thioester, peptide, hydrazone, ester, carbamate or amide
bond;
R 1, R2 , R3 , R4 , R5 , R 6, R7 , R 8, R9 , and Rio are the same or
different and are H, linear alkyl having from 1-6 carbon atoms, branched or
cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic
alkenyl or alkynyl having from 2 to 6 carbon atoms, anions, such as but not 2 limited to, S03 ~. X-S0 3 . OP0 3 2 ~, X-OP0 3 2 ,P0 3 2 , X-P0 3 , C0 2 , cations,
such as but not limited to, a nitrogen containing heterocycle, N+RiiR 12 R1 3 or
X-NRi iR 12 R 3 , or a phenyl, wherein:
RiI, R 12 and R13 are same or different and are H, linear alkyl
having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6
carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6
carbon atoms, or a branched or cyclic alkyl having from 3 to 6 carbon atoms;
1, m and n are 0 or an integer from 1 to 4;
A is a phenyl or substituted phenyl, wherein the substituent is a
linear alkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl
having from 3 to 6 carbon atoms, or a charged substituent selected from 2- 2- 2 anions, such as but not limited to, SO3. X-S03 ~. OP0 32, X-OP0 32, P0 3 -, X
P0 3 2-, C02 ~, cations, such as but not limited to, a nitrogen containing
heterocycle, N*RiiR 12 R 13 or X-NRi iR 21 R 3 , wherein X has the same
definition as above, and wherein g is 0 or 1;
Z is an optional polyethyleneoxy unit of formula (OCH 2 CH 2 )p,
wherein p is 0 or an integer from 2 to about 1000, or F1-El-P-E2-F2 unit in
which El and E2 are the same or different and are C=O,0, or NR14, wherein
R14 is H, a linear alkyl having from 1-6 carbon atoms, a branched or cyclic
alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or
alkynyl having from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20
amino acids in length, wherein El or E2 can be linked to the peptide through
the terminal nitrogen, terminal carbon or through a side chain of one of the
amino acids of the peptide; and Fl and F2 are the same or different and are an
optional polyethyleneoxy unit of formula (OCH2 CH2 )p, wherein p is 0 or an
integer from 2 to about 1000, provided that when Z is not F1-El-P-E2-F2, at
least one of R1 , R2, R3, R 4, R5 , R6 , R7, R8 , R9 , and RIO is a charged substituent
8, R9 , and Rio is 1 , R 2 , R 3, R 4, R5, R6, R7, R or when g is 1, at least one of A, R a
charged substituent;
Y represents a carbonyl, thioether, amide, disulfide, or
hydrazone group; and q is an integer from 1 to 20.
[731 As described in more detail below, the drug can be any of many
small molecule drugs, including, but not limited to, maytansinoids, CC-1065
analogs, morpholinos, doxorubicins, taxanes, cryptophycins, epothilones,
calicheamicins, auristatins, and pyrrolobenzodiazepine dimers.
[741 In preferred embodiments, one of R1 , R2 , R3 , R 4 , R9 , RIO is a
charged substituent selected from sulfonate, phosphate, carboxylate or
trialkylammonium, and the rest are H, 1, g and m are each 0, n = 1, D is a
maytansinoid, a CC-1065 analog or a pyrrolobenzodiazepine dimer. In
another more preferred embodiment, one of R1 , R2, R3, R 4 , R9 , Rio is a sulfonate, and the rest are H, 1, g and m are each 0, n = 1, D is a maytansinoid,
CC-1065 analog or a pyrrolobenzodiazepine dimer linked via a disulfide,
thioester, or thioether bond. In a further more preferred embodiment, one of
R 1, R2, R3, R4, R9 , Rio is a sulfonate, and the rest are H, 1, g and m are each 0,
n = 1, and Q is a maytansinoid, a CC-1065 analog, or a taxane.
[751 In a preferred embodiment, when Z is an F1-El-P-E2-F2 unit,
El and E2 are the same or different and are C=O or NR14, wherein R 14 is H,
a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl having
from 3 to 6 carbon atoms, P is a peptide unit between 2 and 8 amino acids in
length, wherein El or E2 can be linked to the peptide through the terminal
nitrogen, terminal carbon or through a side chain of one of the amino acids of
the peptide, preferred amino acid residues are glycine (gly), alanine (ala),
leucine (leu), glutamic acid (glu), or lysine (lys), which can be used in any
combination or any order (e.g., gly-gly-gly or ala-leu-ala-leu, etc.); and F1 and
F2 are the same or different and are an optional polyethyleneoxy unit of
formula (OCH2 CH2 )p, wherein p is 0 or an integer from 2 to about 1000.
[76] In a more preferred embodiment, when Z is an F1-El-P-E2-F2
unit, El and E2 are the same or different and are C=O or NR14, wherein R 14
is H or a linear alkyl having from 1-6 carbon atoms, P is a peptide unit
between 2 and 5 amino acids in length, wherein El or E2 can be linked to the
peptide through the terminal nitrogen, terminal carbon or through a side chain
of one of the amino acids of the peptide; and F1 and F2 are the same or different and are an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p, wherein p is 0 or an integer from 2 to 24.
[77] Preferably, q, the number of drugs bound to each cell-binding
agent is 1-20, more preferably 2-18, and even more preferably 2-16, and most
preferably 2-10.
[78] To synthesize the conjugate, the cell-binding agent can be
modified with the crosslinkers of the present invention to introduce reactive
disulfide groups, maleimido, haloacetyl or hydrazide groups. Synthesis of the
cell-binding agent-drug conjugates linked via disulfide bonds is achieved by a
disulfide exchange between the disulfide bond in the modified cell-binding
agent and a drug containing a free thiol group. Synthesis of the cell-binding
agent-drug conjugates linked via thioether is achieved by reaction of the
maleimido or haloacetyl modified cell-binding agent and a drug containing a
free thiol group. Synthesis of conjugates bearing an acid labile hydrazone link
can be achieved by reaction of a carbonyl group with the hydrazide moiety in
the linker, by methods known in the art (see, for example, P. Hamann et al.,
BioConjugate Chem., 13; 40-46, 2002; B. Laguzza et al., JMed. Chem., 32;
548-555, 1959; P. Trail et al., Cancer Res., 57; 100-105, 1997).
[79] Alternatively, the drug can be modified with the crosslinkers of
the present invention to give a modified drug of formula (IV) bearing a
functionality capable of reacting with a cell binding agent. For example a
thiol-containing drug can be reacted with the charged or pro-charged crosslinker of formula (I) bearing a maleimdo substituent at neutral pH in aqueous buffer to give a drug connected to the charged linker via a thioether link. A thiol-containg drug can undergo disulfide exchange with a charged linker bearing a pyrdiyldithio moiety to give a modified drug attached via a disulfide bond to the charged crosslinker. A drug bearing a hydroxyl group can be reacted with a charged or pro-charged crosslinker bearing a halogen, in the presence of a mild base, to give a modified drug bearing an ether link. A hydroxyl group containing drug can be condensed with a charged crosslinker of formula (I) bearing a carboxyl group, in the presence of a dehydrating agent, such as dicyclohexylcarbodimide, to give an ester link. An amino group containing drug can similarly undergo condensation with a carboxyl group on the charged or pro-charged crosslinker of formula (I) to give an amide bond.
[80] The conjugate may be purified by standard biochemical means,
such as gel filtration on a Sephadex G25 or Sephacryl S300 column,
adsorption chromatography, and ion exchange or by dialysis as previously
described. In some cases (e.g. folic acid, melanocyte stimulating hormone,
EGF etc) the cell-binding agent-drug conjugates can be purified by
chromatography such as by HPLC, medium pressure column chromatography
or ion exchange.
Modified cell-binding! agents
[811 The cell-binding agent modified by reaction with crosslinkers
of the present invention are preferably represented by the formula (III)
R7 R8 RR33 R P 1 zQ C 1A n
LR.9 ~i RIOR5 R6 I i s"R R2 _qq
wherein the substituents are as described above for the charged
or pro-charged linker and the cell-binding agent drug conjugate.
[82] In preferred embodiments, one of R1 , R2 , R3 , R 4 , R9 , RIO is a
charged substituent selected from sulfonate, phosphate, carboxyl or
trialkylammonium, and the rest are H, 1, g and m are each 0, n = 1, Q is a
disulfide substituent, a maleimido, haloacetyl group, or a N-hydroxy
succinimide ester, and Y is thioether, amide, or disulfide. In another more
preferred embodiment, one of R1, R2, R3, R4 , R9, RIO is a sulfonate, and the
rest are H, 1, g and m are each 0, n = 1, Q is a disulfide, maleimido or
haloacetyl moiety, and Y is thioether, amide, or disulfide. In a further more
preferred embodiment, one of R1, R2, R 3, R4 , R9 , RIO is a sulfonate, and the
rest are H, 1, g and m are each 0, n = 1, Q is a pyridyldithio or
nitropyridyldithio group, and Y is thioether, amide, or disulfide.
[831 In a preferred embodiment, when Z is an F1-El-P-E2-F2 unit,
El and E2 are the same or different and are C=0 or NR14, wherein R 14 is H,
a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl having
from 3 to 6 carbon atoms, P is a peptide unit between 2 and 8 amino acids in
length, wherein El or E2 can be linked to the peptide through the terminal
nitrogen, terminal carbon or through a side chain of one of the amino acids of
the peptide, preferred amino acid residues are glycine (gly), alanine (ala),
leucine (leu), glutamic acid (glu), or lysine (lys), which can be used in any
combination or any order (e.g., gly-gly-gly or ala-leu-ala-leu, etc.); and Fl and
F2 are the same or different and are an optional polyethyleneoxy unit of
formula (OCH 2 CH2 )p, wherein p is 0 or an integer from 2 to about 1000.
[841 In a more preferred embodiment, when Z is an FI-El-P-E2-F2
unit, El and E2 are the same or different and are C=O or NR14, wherein R 14
is H or a linear alkyl having from 1-6 carbon atoms, P is a peptide unit
between 2 and 5 amino acids in length, wherein El or E2 can be linked to the
peptide through the terminal nitrogen, terminal carbon or through a side chain
of one of the amino acids of the peptide; and Fl and F2 are the same or
different and are an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p,
wherein p is 0 or an integer from 2 to 24.
[851 The modified cell-binding agent can be prepared by reacting
the cell-binding agent with the charged crosslinkers by methods known in the
art for other crosslinkers (U.S. Patent Nos. 6,340,701 B1, 5,846,545,
5,585,499, 5,475,092, 5,414,064, 5,208,020, and 4,563,304; R.V.J. Chari et al.
Cancer Research 52, 127-131, 1992; R.V.J. Chari et al. CancerResearch 55,
4079-4084, 1995; J. Carlsson et al. 173 Biochem. J (1978) 723-737(1978);
Goff, D. A., Carroll, S. F. 1 BioConjugate Chem. 381-386 (1990); L. Delprino
et al. 82 J. Pharm. Sci. 506-512 (1993); S. Arpicco et al., 8 BioConjugate
Chem 327-337 (1997)). Advantageously, because the cross-linker groups are
soluble in water or require only a small percentage of organic solvent to
maintain solubility in aqueous solution, the reaction between the cell-binding
agent and the cross-linker can be conducted in aqueous solution. The cross
linking reagent is dissolved in aqueous buffer, optionally containing a small
amount (typically <10% by volume) of a polar organic solvent that is miscible
with water, for example different alcohols, such as methanol, ethanol, and
propanol, dimethyl formamide, dimethyl acetamide, or dimethylsulfoxide at a
high concentration, for example 1-100 mM, and then an appropriate aliquot is
added to the buffered aqueous solution of the cell-binding agent. An
appropriate aliquot is an amount of solution that introduces 1-10 cross-linking
groups per cell-binding agent, preferably 1-5 groups, and the volume to be
added should not exceed 10 %, preferably 5 %, and most preferably 0-3 % of
the volume of the cell-binding agent solution. The aqueous solutions for the
cell-binding agents are buffered between pH 6 and 9, preferably between 6.5
and 7.5 and can contain any non-nucleophilic buffer salts useful for these pH
ranges. Typical buffers include phosphate, triethanolamine.HCl, HEPES, and
MOPS buffers, which can contain additional components, such as sucrose and
salts, for example, NaCl. After the addition the reaction is incubated at a
temperature of from 4 C to 40 °C, preferably at ambient temperature. The
progress of the reaction can be monitored by measuring the increase in the
absorption at 495 nm or another appropriate wavelength. After the reaction is
complete, isolation of the modified cell-binding agent can be performed in a
routine way, using for example gel filtration chromatography, or adsorptive
chromatography.
[86] The extent of modification can be assessed by measuring the
absorbance of the nitropyridine thione, dinitropyridine dithione,
carboxamidopyridine dithione or dicarboxamidopyridine dithione group
released. In a non limiting example, Figure 56 shows the results from the
modification of the cell-binding agent, the C242 antibody, with a sulfonate
crosslinker of the present invention. The time course of linker/antibody (L/A)
incorporation is shown, for example, along with the drugs/antibody (D/A)
linked. The charged or pro-charged crosslinkers described herein have
diverse functional groups that can react with any cell-binding agent that
possesses a suitable substituent. For example cell-binding agents bearing an
amino or hydroxyl substituent can react with crosslinkers bearing an
N-hydroxysuccinimide ester, cell-binding agents bearing a thiol substituent
can react with crosslinkers bearing a maleimido or haloacetyl group.
Additionally, cell-binding agents bearing a carbonyl substituent can react with crosslinkers bearing a hydrazide. One skilled in the art can readily determine which crosslinker to use based on the known reactivity of the available functional group on the cell-binding agent.
[87] Crosslinkers bearing a positive charge (for example, compound
214, Figure 71) can be directly reacted with a cell binding agent in aqueous
buffer at a pH between 5 and 9, optionally containing an organic cosolvent
(such as 1 to 20% dimethylaceatmide or ethanol) to provide a modified cell
binding agent bearing a positive charge and a thiol group. The thiol group of
the cell binding agent can be reacted with a cytotoxic drug bearing either a
maleimido, haloacetamido or an active disulfide (example pyridyldithio,
nitropyridyldithio group) to provide a conjugate. The conjugate can be
purified by the methods described above.
[881 Alternatively, crosslinkers bearing a positive charge and a
reactive ester (for example, compound 216, Figure 71) can be directly reacted
with a cell binding agent (for example, through its lysine amino group) to
introduce a positive charge and an active disulfide. Reaction with a thiol
containing cytotoxic drug as described above can provide a conjugate bearing
a positive charge.
Modified Cytotoxic Drugs
[89] The cytotoxic drugs modified by reaction with crosslinkers of
the present invention are preferably represented by the formula (IV):
R 7 Ru R R4 Y' ZN D Ag m R 9 RIO R5 R6 R1 R2
wherein the substituents are as described above for the charged
or pro-charged linker and the cell-binding agent drug conjugate.
[901 In preferred embodiments, one of R1 , R2, R3, R 4 , R9 , RIO is a
charged substituent selected from sulfonate, phosphate, carboxyl or
trialkylammonium, and the rest are H, 1, g and m are each 0, n = 1, and Y' is a
disulfide substituent, a maleimido, haloacetyl group, or a N-hydroxy
succinimide ester. In another more preferred embodiment, one of R1 , R2, R3 ,
R4, R9, RIO is a sulfonate, and the rest are H, 1, g and m are each 0, n = 1, and
Y' is a maleimido moiety or a N-hydroxy succinimide ester. In a further more
preferred embodiment, one of R1, R2, R3, R 4, R9, RIO is a sulfonate, and the
rest are H, 1, g and m are each 0, n = 1, and Y' is a N-hydroxy succinimide
ester.
[91] In a preferred embodiment, when Z is an F1-El-P-E2-F2 unit,
El and E2 are the same or different and are C=O or NR14, wherein R 14 is H,
a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl having
from 3 to 6 carbon atoms, P is a peptide unit between 2 and 8 amino acids in
length, wherein El or E2 can be linked to the peptide through the terminal
nitrogen, terminal carbon or through a side chain of one of the amino acids of
the peptide, preferred amino acid residues are glycine (gly), alanine (ala),
leucine (leu), glutamic acid (glu), or lysine (lys), which can be used in any
combination or any order (e.g., gly-gly-gly or ala-leu-ala-leu, etc.); and Fl and
F2 are the same or different and are an optional polyethyleneoxy unit of
formula (OCH2 CH 2 )p, wherein p is 0 or an integer from 2 to about 1000.
[92] In a more preferred embodiment, when Z is an F1-El-P-E2-F2
unit, El and E2 are the same or different and are C=O or NR14, wherein R 14
is H or a linear alkyl having from 1-6 carbon atoms, P is a peptide unit
between 2 and 5 amino acids in length, wherein El or E2 can be linked to the
peptide through the terminal nitrogen, terminal carbon or through a side chain
of one of the amino acids of the peptide; and Fl and F2 are the same or
different and are an optional polyethyleneoxy unit of formula (OCH 2 CH2)p,
wherein p is 0 or an integer from 2 to 24.
[93] The modified drugs can be prepared by reacting the drug with
the crosslinkers of the present invention to give a modified drug of formula
(IV) bearing a functionality capable of reacting with a cell binding agent. For example a thiol-containing drug can be reacted with the charged or pro charged crosslinker of formula (I) bearing a maleimdo substituent at neutral pH in aqueous buffer to give a drug connected to the charged or pro-charged linker via a thioether link. A thiol-containg drug can undergo disulfide exchange with a charged or pro-charged linker bearing a pyrdiyldithio moiety to give a modified drug attached via a disulfide bond to the charged or pro charged crosslinker. A drug bearing a hydroxyl group can be reacted with a charged crosslinker bearing a halogen, in the presence of a mild base, to give a modified drug bearing an ether link. A hydroxyl group containing drug can be condensed with a charged crosslinker of formula (I) bearing a carboxyl group, in the presence of a dehydrating agent, such as dicyclohexylcarbodimide, to give an ester link. An amino group containing drug can similarly undergo condensation with a carboxyl group on the charged or pro-charged crosslinker of formula (I) to give an amide bond. The modified drug can be purified by standard methods such as column chromatography over silica gel or alumina, crystallization, preparatory thin layer chromatography, ion exchange chromatography or HPLC.
Cell-binding Agents
[94] The cell-binding agent that comprises the conjugates and the
modified cell-binding agents of the present invention may be of any kind
presently known, or that become known, and includes peptides and non-peptides.
The cell-binding agent may be any compound that can bind a cell, either in a
specific or non-specific manner. Generally, these can be antibodies (especially
monoclonal antibodies and antibody fragments), adnectins (US Publication No.:
20070082365), interferons, lymphokines, hormones, growth factors, vitamins,
nutrient-transport molecules (such as transferrin), or any other cell-binding
molecule or substance.
[95] Where the cell-binding agent is an antibody (for example, a
murine, human humanized, resurfaced or a chimeric or any other antibody
known to one of skill in the art), it binds to an antigen that is a polypeptide and
may be a transmembrane molecule (e.g. receptor) or a ligand such as a growth
factor. Exemplary antigens include molecules such as renin; a growth
hormone, including human growth hormone and bovine growth hormone;
growth hormone releasing factor; parathyroid hormone; thyroid stimulating
hormone; lipoproteins; alpha-1-antitrypsin; insulin A-chain; insulin B-chain;
proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone;
glucagon; clotting factors such as factor vmc, factor IX, tissue factor (TF), and
von Willebrands factor; anti-clotting factors such as Protein C; atrial
natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase
or human urine or tissue-type plasminogen activator (t-PA); bombesin;
thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and -beta;
enkephalinase; RANTES (regulated on activation normally T-cell expressed
and secreted); human macrophage inflammatory protein (MIP-1-alpha); a serum albumin, such as human serum albumin; Muellerian-inhibiting substance; relaxin A-chain; relaxin B-chain; prorelaxin; mouse gonadotropin associated peptide; a microbial protein, such as beta-lactamase; DNase; IgE; a cytotoxic T-lymphocyte associated antigen (CTLA), such as CTLA-4; inhibin; activin; vascular endothelial growth factor (VEGF); receptors for hormones or growth factors; protein A or D; rheumatoid factors; a neurotrophic factor such as bone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5, or -6
(NT-3, NT4, NT-5, or NT-6), or a nerve growth factor such as NGF-p;
platelet-derived growth factor (PDGF); fibroblast growth factor such as aFGF
and bFGF; epidermal growth factor (EGF); transforming growth factor (TGF)
such as TGF-alpha and TGF-beta, including TGF-1, TGF-2, TGF- P3,
TGF-p4, or TGF- P5; insulin-like growth factor-I and -II (IGF-I and IGF-II);
des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins,
EpCAM, GD3, FLT3, PSMA, PSCA, MUC1, MUC16, STEAP, CEA,
TENB2, EphA receptors, EphB receptors, folate receptor, mesothelin, cripto,
alphavbeta, integrins, VEGF, VEGFR, tarnsferrin receptor, IRTA1, IRTA2,
IRTA3, IRTA4, IRTA5; CD proteins such as CD2, CD3, CD4, CD5, CD6,
CD8, CD11, CD14, CD19, CD20, CD21, CD22, CD23, CD25, CD26, CD28,
CD30, CD33, CD36, CD37, CD38, CD40, CD44, CD52, CD55, CD56, CD59,
CD70, CD79, CD80, CD81, CD103, CD105, CD134, CD137, CD138, CD152
or an antibody which binds to one or more tumor-associated antigens or cell
surface receptors disclosed in US Publication No. 20080171040 or US
Publication No. 20080305044 and are incorporated in their entirety by
reference; erythropoietin; osteoinductive factors; immunotoxins; a bone
morphogenetic protein (BMP); an interferon, such as interferon-alpha, -beta,
and -gamma; colony stimulating factors (CSFs), e.g., M-CSF, GM-CSF, and
G-CSF; interleukins (ILs), e.g., IL-1 to IL-10; superoxide dismutase; T-cell
receptors; surface membrane proteins; decay accelerating factor; viral antigen
such as, for example, a portion of the HIV envelope; transport proteins;
homing receptors; addressins; regulatory proteins; integrins, such as CD11a,
CD11b, CD11c, CD18, an ICAM, VLA-4, EpCAM and VCAM; a tumor
associated antigen such as HER2, HER3 or HER4 receptor; and fragments of
any of the above-listed polypeptides.
[96] Preferred antigens for antibodies encompassed by the present
invention also include CD proteins, such as CD3, CD4, CD8, CD19, CD20,
CD34, and CD46; members of the ErbB receptor family, such as the EGF
receptor, HER2, HER3 or HER4 receptor; cell adhesion molecules, such as
LFA-1, Maci, p150.95, VLA-4, ICAM-1, VCAM, EpCAM, alpha 4/beta7
integrin, and alpha v/beta3 integrin including either alpha or beta subunits
thereof (e.g. anti-CD11a, anti-CD18 or anti-CD11b antibodies); growth
factors, such as VEGF; tissue factor (TF); TGF-P.; alpha interferon (alpha
IFN); an interleukin, such as IL-8; IgE; blood group antigens Apo2, death
receptor; flk2/ft3 receptor; obesity (OB) receptor; mpl receptor; CTLA-4;
protein C etc. Preferred antibodies that can be used are antibodies to CD2,
CD3, CD4, CD5, CD6, CD11, CD19, CD20, CD22, CD26, CD30, CD33,
CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, EphA receptors
(e.g., EphA2 receptor), EphB receptors, EGFr, EGFRvIII, HER2, HER3,
trastuzumab, pertuzumab mesothelin, cripto, alphavbeta, integrins, VEGF,
VEGFR, folate receptor (for example, FOLR1), transferrin receptor, GD3,
EpCAM or an antibody which binds to one or more tumor-associated antigens
or cell-surface receptors disclosed in US Publication No. 20080171040 or US
Publication No. 20080305044 and are incorporated in their entirety by
reference.
[97] Additional examples of cell-binding agents that can be used
include:
-resurfaced antibodies (U.S. patent no. 5,639,641);
-humanized or fully human antibodies, selected from but not
limited to, huMy9-6, huB4, huC242, huN901, DS6, CD38, IGF-IR, CNTO 95,
B-B4, trastuzumab, pertuzumab, bivatuzumab, sibrotuzumab, and rituximab
(see, e.g., U.S. Patent Nos. 5,639,641, 5,665,357; and 7,342,110, U.S.
Provisional Patent Application No. 60/424,332, International Patent
Application WO 02/16,401, U.S. Patent Publication Number 20060045877,
U.S. Patent Publication Number 20060127407, U.S. Patent Publication
Number 20050118183, Pedersen et al., (1994) J Mol. Biol. 235, 959-973,
Roguska et al., (1994) Proceedingsof the NationalAcademy ofSciences, Vol
91, 969-973, supra, Colomer et al., Cancer Invest., 19: 49-56 (2001), Heider et al., Eur. J Cancer, 31A: 2385-2391 (1995), Welt et al., J. Clin. Oncol., 12:
1193-1203 (1994), and Maloney et al., Blood, 90: 2188-2195 (1997)); and
-epitope-binding fragments of antibodies such as sFv, Fab,
Fab', and F(ab') 2 (Parham, J Immunol. 131:2895-2902 (1983); Spring et al, J
Immunol. 113:470-478 (1974); Nisonoff et al, Arch. Biochem. Biophys.
89:230-244 (1960)).
Additional cell-binding agents include other cell-binding proteins and
polypeptides exemplified by, but not limited to:
- Ankyrin repeat proteins (DARPins; Zahnd et al., J. Biol.
Chem., 281, 46, 35167-35175, (2006); Binz, H.K., Amstutz, P. & Pluckthun,
A. (2005) Nature Biotechnology, 23, 1257-1268) or ankyrin-like repeats
proteins or synthetic peptides described, for example, in U.S. Patent
Publication Number 20070238667; U.S. Patent No. 7,101,675; and
WO/2007/147213; WO/2007/062466);
-interferons (e.g. a, P, y);
-lymphokines such as IL-2, IL-3, IL-4, IL-6;
-hormones such as insulin, TRH (thyrotropin releasing
hormones), MSH (melanocyte-stimulating hormone), steroid hormones, such
as androgens and estrogens;
-vitamins such as folic acid;
-growth factors and colony-stimulating factors such as EGF,
TGF-a, G-CSF, M-CSF and GM-CSF (Burgess, Immunology Today 5:155
158 (1984)); and
-transferrin (O'Keefe et al, J Biol. Chem. 260:932-937 (1985)).
[98] Monoclonal antibody techniques allow for the production of
specific cell-binding agents in the form of monoclonal antibodies. Particularly
well known in the art are techniques for creating monoclonal antibodies
produced by immunizing mice, rats, hamsters or any other mammal with the
antigen of interest such as the intact target cell, antigens isolated from the
target cell, whole virus, attenuated whole virus, and viral proteins such as viral
coat proteins. Sensitized human cells can also be used. Another method of
creating monoclonal antibodies is the use of phage libraries of sFv (single
chain variable region), specifically human sFv (see, e.g., Griffiths et al, U.S.
Patent No. 5,885,793; McCafferty et al, WO 92/01047; and Liming et al,
WO 99/06587.)
[991 Selection of the appropriate cell-binding agent is a matter of
choice that depends upon the particular cell population that is to be targeted,
but in general monoclonal antibodies and epitope binding fragments thereof
are preferred, if an appropriate one is available.
[1001 For example, the monoclonal antibody My9 is a murine IgG 2a
antibody that is specific for the CD33 antigen found on Acute Myeloid
Leukemia (AML) cells (Roy et al. Blood 77:2404-2412 (1991)) and can be used to treat AML patients. Similarly, the monoclonal antibody anti-B4 is a murine IgG1, which binds to the CD19 antigen on B cells (Nadler et al, J.
Immunol. 131:244-250 (1983)) and can be used if the target cells are B cells or
diseased cells that express this antigen such as in non-Hodgkin's lymphoma or
chronic lymphoblastic leukemia. Similarly, the antibody N901 is a murine
monoclonal IgG1 antibody that binds to CD56 found on small cell lung
carcinoma cells and on cells of other tumors of the neuroendocrine origin (Roy
et al. J Nat. Cancer Inst. 88:1136-1145 (1996)), C242 antibody that binds to
the CanAg antigen, pertuzumab, trastuzumab that binds to HER2/neu, and
anti-EGF receptor antibody.
[101] Additionally, GM-CSF, which binds to myeloid cells, can be
used as a cell-binding agent to diseased cells from acute myelogenous
leukemia. IL-2, which binds to activated T-cells, can be used for prevention of
transplant graft rejection, for therapy and prevention of graft-versus-host
disease, and for treatment of acute T-cell leukemia. MSH, which binds to
melanocytes, can be used for the treatment of melanoma. Folic acid, which
targets the folate receptor expressed on ovarian and other cancers is also a
suitable cell-binding agent.
[102] Cancers of the breast and testes can be successfully targeted
with estrogen (or estrogen analogues) or androgen (or androgen analogues),
respectively, as cell-binding agents.
Drugs
[103] Drugs that can be used in the present invention include
chemotherapeutic agents. "Chemotherapeutic agent" is a chemical compound
useful in the treatment of cancer. Examples of chemotherapeutic agents
include alkylating agents, such as thiotepa and cyclophosphamide
(CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and
uredopa; ethylenimines and methylamelamines including altretamine,
triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide
and trimethylolomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including the synthetic analogue topotecan);
bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and
bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and
cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues,
KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,
cholophosphamide, estramustine, ifosfamide, mechlorethamine,
mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine,
prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine,
chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics,
such as the enediyne antibiotics (e.g. calicheamicin, especially calicheamicin
.gammaland calicheamicin theta I, see, e.g., Angew Chem Intl. Ed. Engl.
33:183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimnidine analogs such as, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals, such as aminoglutethimide, mitotane, trilostane; folic acid replenisher, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK*; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,
2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A,
roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine;
mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOL*, Bristol-Myers
Squibb Oncology, Princeton, N.J.) and doxetaxel (TAXOTERE*, Rhone
Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin and
carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin
C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide;
daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase
inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoic acid;
capecitabine; and pharmaceutically acceptable salts, acids or derivatives of
any of the above. Also included in this definition are anti-hormonal agents
that act to regulate or inhibit hormone action on tumors, such as anti-estrogens
including for example tamoxifen, raloxifene, aromatase inhibiting
4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and toremifene (Fareston); and anti-androgens, such as flutamide,
nilutamide, bicalutamide, leuprolide, and goserelin; siRNA and
pharmaceutically acceptable salts, acids or derivatives of any of the above.
Other chemotherapeutic agents that can be used with the present invention are
disclosed in US Publication No. 20080171040 or US Publication No.
20080305044 and are incorporated in their entirety by reference.
[1041 In a preferred embodiment, chemotherapeutic drugs are
essentially small molecule drugs. A "small molecule drug" is broadly used
herein to refer to an organic, inorganic, or organometallic compound that may
have a molecular weight of for example 100 to 1500, more suitably from 120
to 1200, favorably from 200 to 1000, and typically having a molecular weight
of less than about 1000. Small molecule drugs of the invention encompass
oligopeptides and other biomolecules having a molecular weight of less than
about 1000. Small molecule drugs are well characterized in the art, such as in
W005058367A2, European Patent Application Nos. 85901495 and 8590319,
and in U.S. Patent No. 4,956,303, among others and are incorporated in their
entirety by reference.
[105] Preferable small molecule drugs are those that allow for linkage
to the cell-binding agent. The invention includes known drugs as well as those
that may become known. Especially preferred small molecule drugs include
cytotoxic agents.
[106] The cytotoxic agent may be any compound that results in the
death of a cell, or induces cell death, or in some manner decreases cell
viability, wherein each cytotoxic agent comprises a thiol moiety.
[1071 Preferred cytotoxic agents are maytansinoid compounds, taxane
compounds, CC-1065 compounds, daunorubicin compounds and doxorubicin
compounds, pyrrolobenzodiazepine dimers, calicheamicins. Auristatins and
analogues and derivatives thereof, some of which are described below.
[108] Other cytotoxic agents, which are not necessarily small
molecules, such as siRNA, are also encompassed within the scope of the
instant invention. For example, siRNAs can be linked to the crosslinkers of
the present invention by methods commonly used for the modification of
oligonucleotides (see, for example, US Patent Publications 20050107325 and
20070213292). Thus the siRNA in its 3' or 5'-phosphoromidite form is
reacted with one end of the crosslinker bearing a hydroxyl functionality to
give an ester bond between the siRNA and the crosslinker. Similarly reaction
of the siRNA phosphoramidite with a crosslinker bearing a terminal amino
group results in linkage of the crosslinker to the siRNA through an amine.
siRNA are described in detail in U.S. Patent Publication Numbers:
20070275465,20070213292,20070185050,20070161595,20070054279,
20060287260,20060035254,20060008822,20050288244,20050176667,
which are incorporated herein in their entirety by reference.
Maytansinoids
[109] Maytansinoids that can be used in the present invention are
well known in the art and can be isolated from natural sources according to
known methods or prepared synthetically according to known methods.
[110] Examples of suitable maytansinoids include maytansinol and
maytansinol analogues. Examples of suitable maytansinol analogues include
those having a modified aromatic ring and those having modifications at other
positions.
[111] Specific examples of suitable analogues of maytansinol having
a modified aromatic ring include:
(1) C-19-dechloro (U.S. Patent No. 4,256,746) (prepared by
LAH reduction of ansamitocin P2);
(2) C-20-hydroxy (or C-20-demethyl)+/-C-19-dechloro (U.S.
Patent Nos. 4,361,650 and 4,307,016) (prepared by demethylation using
Streptomyces or Actinomyces or dechlorination using LAH); and
(3) C-20-demethoxy, C-20-acyloxy (-OCOR), +/-dechloro
(U.S. Patent No. 4,294,757) (prepared by acylation using acyl chlorides).
[112] Specific examples of suitable analogues of maytansinol having
modifications of other positions include:
(1) C-9-SH (U.S. Patent No. 4,424,219) (prepared by the
reaction of maytansinol with H2S or P2S5);
(2) C-14-alkoxymethyl (demethoxy/CH2OR) (U.S. Patent No.
4,331,598);
(3) C-14-hydroxymethyl or acyloxymethyl (CH2OH or
CH20Ac) (U.S. Patent No. 4,450,254) (prepared from Nocardia);
(4) C-15-hydroxy/acyloxy (U.S. Patent No. 4,364,866)
(prepared by the conversion of maytansinol by Streptomyces);
(5) C-15-methoxy (U.S. Patent Nos. 4,313,946 and 4,315,929)
(isolated from Trewia nudiflora);
(6) C-18-N-demethyl (U.S. Patent Nos. 4,362,663 and
4,322,348) (prepared by the demethylation of maytansinol by Streptomyces);
and
(7) 4,5-deoxy (U.S. Patent No. 4,371,533) (prepared by the
titanium trichloride/LAH reduction of maytansinol).
[1131 The synthesis of thiol-containing maytansinoids useful in the
present invention is fully disclosed in U.S. Patent Nos. 5,208,020, 5,416,064,
and U. S. Patent Application No. 20040235840.
[1141 Maytansinoids with a thiol moiety at the C-3 position, the C-14
position, the C-15 position or the C-20 position are all expected to be useful.
The C-3 position is preferred and the C-3 position of maytansinol is especially
preferred. Also preferred are an N-methyl-alanine-containing C-3 thiol moiety
maytansinoid, and an N-methyl-cysteine-containing C-3 thiol moiety
maytansinoid, and analogues of each.
[1151 Specific examples of N-methyl-alanine-containing C-3 thiol
moiety maytansinoid derivatives useful in the present invention are
represented by the formulae M1, M2, M3, M6 and M7.
CH 3 0
N (CH 2)1SH
0 CH 3
May
M1
wherein:
1 is an integer of from 1 to 10; and
may is a maytansinoid.
CH, 0 R, R2
CH-CH-(CH 2)mSH N ) CH 3
May M2
wherein:
Ri and R2 are H, CH3 or CH2 CH3 , and may be the same or different;
m is 0, 1, 2 or 3; and
may is a maytansinoid.
00 ON (CH 2), SH
fhay
M3 wherein: n is an integer of from 3 to 8; and may is a maytansinoid.
0 0 (CH2)/SH X3O N) N OO O
NH O MeO M6
wherein:
lis1,2or3;
Yo is Cl or H; and
X 3 is H or CH 3 .
CH 3 0 0 I N H-CH-(CR 3R 4)mSH 0 CH 3 May M7
wherein:
R 1, R2, R3 , R4 are H, CH 3 or CH2CH 3, and may be the same or
different; mis0, 1,2 or3; and may is a maytansinoid.
[1161 Specific examples of N-methyl-cysteine-containing C-3 thiol
moiety maytansinoid derivatives useful in the present invention are
represented by the formulae M4 and M5.
SH (OH 3 )o O
N (CH 2 )pCH 3
f-nay M4
wherein:
ois1,2or3;
p is an integer of 0 to 10; and
may is a maytansinoid.
SH (CH 2)0o 0 N (CH 2)qCH 3
NH _OH O MeO M5
wherein:
ois1,2or3;
q is an integer of from 0 to 10;
Yo is Cl or H; and
X 3 is H or CH3 .
Preferred maytansinoids are those described in U.S. Patent Nos.
5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821; RE39,151 and
7,276,497.
Taxanes
[117] The cytotoxic agent according to the present invention may
also be a taxane.
[118] Taxanes that can be used in the present invention have been
modified to contain a thiol moiety. Some taxanes useful in the present
invention have the formula T1 shown below:
R2 0 0 OR5 O
R4""' NH 10 9 876 I1
1 4 O 0 15 R3
OR 6
0
Rl' I, 1 T1
[119] Four embodiments of these novel taxanes are described below.
[120] In embodiments (1), (2), (3), and (4), R 1, Ri', and Ri" are the
same or different and are H, an electron withdrawing group, such as F, NO 2
, CN, Cl, CHF2, or CF 3 or an electron donating group, such as -OCH 3
-OCH2CH 3, -NR7R, -OR 9, wherein R 7 and R 8are the same or different and , are linear, branched, or cyclic alkyl groups having 1 to 10 carbon atoms or
simple or substituted aryl having 1 to 10 carbon atoms. Preferably the number
of carbon atoms for R 7 and R 8 is 1 to 4. Also, preferably R7 and R8 are the
same. Examples of preferred -NR7R8 groups include dimethyl amino, diethyl
amino, dipropyl amino, and dibutyl amino, where the butyl moiety is any of
primary, secondary, tertiary or isobutyl. R9 is linear, branched or cyclic alkyl
having 1 to 10 carbon atoms.
[121] R 1 preferably is OCH3 ,F, NO 2 , or CF3 .
[122] Also preferably, R 1 is in the meta position and R 1' and R1 " are
H or OCH 3 .
[123] R2 in embodiments (1), (2) and (4), is H, heterocyclic, a linear,
branched, or cyclic ester having from 1 to 10 carbon atoms or heterocyclic, a
linear, branched, or cyclic ether having from 1 to 10 carbon atoms or a
carbamate of the formula -CONRIORI, wherein RIO and R 1 are the same or
different and are H, linear alkyl having from 1-6 carbon atoms, branched, or
cyclic alkyl having 3 to 10 atoms or simple or substituted aryl having 6 to 10
carbon atoms. For esters, preferred examples include -COCH 2CH3 and
-COCH2CH 2CH3 . For ethers, preferred examples include -CH2CH3 and
-CH2 CH2CH 3. For carbamates, preferred examples include -CONHCH 2 CH3,
CONHCH 2 CH2CH 3, -CO-morpholino, -CO-piperazino, -CO-piperidino, or
CO-N-methylpiperazino.
[1241 R2 in embodiment (3), is a thiol-containing moiety.
[125] R3 in embodiments (1), (3) and (4), is aryl, or is linear,
branched or cyclic alkyl having 1 to 10 carbon atoms, preferably
-CH 2CH(CH 3) 2 .
[126] R3 in embodiment (2), is -CH=C(CH 3)2 .
[127] R4 in all four embodiments, is -OC(CH 3) 3 or -C 6H 5 .
[128] R5 in embodiments (1) and (2), is a thiol-containing moiety and
R6 has the same definition as above for R2 for embodiments (1), (2) and (4).
[129] R5 and R6 in embodiment (3), are the same or different, and
have the same definition as above for R2 for embodiments (1), (2) and (4).
[1301 R5 in embodiment (4), has the same definition as above for R2
for embodiments (1), (2) and (4) and R6 is a thiol moiety.
[1311 The preferred positions for introduction of the thiol-containing
moiety are R2 and R5 , with R2 being the most preferred.
[132] The side chain carrying the thiol moiety can be linear or
branched, aromatic or heterocyclic. One of ordinary skill in the art can readily
identify suitable side chains. Specific examples of thiol moieties include
-(CH 2)nSH, -CO(CH 2)nSH, -(CH 2)nCH(CH3)SH, -CO(CH 2)nCH(CH 3)SH,
-(CH 2)nC(CH 3)2 SH, -CO(CH 2)nC(CH3)2 SH, -CONR 2(CH2 )nSH,
-CONR 1 2(CH 2)nCH(CH 3)SH, or -CONR 12(CH 2)nC(CH 3)2 SH, -CO
morpholino-XSH, -CO-piperazino-XSH, -CO-piperidino-XSH, and -CO-N
methylpiperazino-XSH wherein
X is a linear alkyl or branched alkyl having 1-10 carbon atoms.
R 12 is a linear alkyl, branched alkyl or cyclic alkyl having 1 to
10 carbon atoms, or simple or substituted aryl having from 1 to 10 carbon
atoms or heterocyclic, and can be H, and
n is an integer of 0 to 10.
[133] Examples of linear alkyls include methyl, ethyl, propyl, butyl,
pentyl and hexyl.
[1341 Examples of branched alkyls include isopropyl, isobutyl,
sec.-butyl, tert.-butyl, isopentyl and 1-ethyl-propyl.
[135] Examples of cyclic alkyls include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
[1361 Examples of simple aryls include phenyl and naphthyl.
[137] Examples of substituted aryls include aryls such as those
described above substituted with alkyl groups, with halogens, such as Cl, Br,
F, nitro groups, amino groups, sulfonic acid groups, carboxylic acid groups,
hydroxy groups or alkoxy groups.
[138] Examples of heterocyclics are compounds wherein the
heteroatoms are selected from 0, N, and S, and include morpholino,
piperidino, piperazino, N-methylpiperazino, pyrrollyl, pyridyl, furyl and
thiophene.
[1391 The taxanes having a thiol moiety can be synthesized according
to known methods. The starting material for the synthesis is the commercially
available 10-deacetylbaccatin III. The chemistry to introduce various
substituents is described in several publications (Ojima et al, J Med Chem.
39:3889-3896 (1996); Ojima et al., J Med Chem. 40:267-278 (1997); Ojima
et al., Proc. Nat. Acad Sci., 96:4256-4261 (1999); U.S. Patent No. 5,475,011
and U.S. Patent No. 5,811,452).
[140] The substituent R 1 on the phenyl ring and the position of the
substituent R 1 can be varied until a compound of the desired toxicity is
obtained. Furthermore, the degree of substitution on the phenyl ring can be
varied to achieve a desired toxicity. That is, the phenyl ring can have one or more substituents (e.g., mono-, di-, or tri-substitution of the phenyl ring) which provide another means for achieving a desired toxicity. One of ordinary skill in the art can determine the appropriate chemical moiety for R1 and the appropriate position for R1 using only routine experimentation.
[1411 For example, electron withdrawing groups at the meta position
increase the cytotoxic potency, while substitution at the para position is not
expected to increase the potency as compared to the parent taxane. Typically,
a few representative taxanes with substituents at the different positions (ortho,
meta and para) will be initially prepared and evaluated for in vitro
cytotoxicity.
[142] The thiol moiety can be introduced at one of the positions
where a hydroxyl group already exists. The chemistry to protect the various
hydroxyl groups, while reacting the desired one, has been described previously
(see, for example, the references cited supra). The substituent is introduced
by simply converting the free hydroxyl group to a disulfide-containing ether, a
disulfide-containing ester, or a disulfide-containing carbamate. This
transformation is achieved as follows. The desired hydroxyl group is
deprotonated by treatment with the commercially-available reagent lithium
hexamethyldisilazane (1.2 equivalents) in tetrahydrofuran at -40°C as
described in Ojima et al. (1999), supra. The resulting alkoxide anion is then
reacted with an excess of a dihalo compound, such as dibromoethane, to give a
halo ether. Displacement of the halogen with a thiol (by reaction with potassium thioacetate and treatment with mild base or hydroxylamine) will provide the desired thiol-containing taxane.
[143] Alternatively, the desired hydroxyl group can be esterified
directly by reaction with an acyl halide, such as 3-bromopropionyl chloride, to
give a bromo ester. Displacement of the bromo group by treatment with
potassium thioacetate and further processing as described above will provide
the thiol-containing taxane ester. Preferred taxoids are those described in U.S.
Patent Nos. 6,340,701; 6,372,738; 6.436,931; 6,596,757; 6,706,708;
7,008,942; 7,217,819 and 7,276,499.
CC-1065 analogues
[144] The cytotoxic agent according to the present invention may
also be a CC-1065 analogue.
[1451 According to the present invention, the CC-1065 analogues
contain an A subunit and a B or a B-C subunit. The A subunits are CPI
(cyclopropapyrroloindole unit) in its natural closed cyclopropyl form or in its
open chloromethyl form, or the closely related CBI unit
(cyclopropylbenzindole unit) in the closed cyclopropyl form or the open
chloromethyl form. The B and C subunits of CC-1065 analogues are very
similar and are 2-carboxy-indole and 2-carboxy-benzofuran derivatives. For
activity, the analogues of CC-1065 need at least one such 2-carboxy-indole
subunit or 2-carboxy-benzofuran subunit, although two subunits (i.e., B-C)
render the analogue more potent. As is obvious from the natural CC-1065 and from the analogues published (e.g., Warpehoski et al, J Med. Chem.
31:590-603 (1988), D. Boger et al., J. Org. Chem; 66; 6654-6661, 2001; U. S.
Patent Nos 5,739,350; 6,060,608; 6.310.209), the B and C subunits can also
carry different substituents at different positions on the indole or benzofuran
rings.
[146] CC-1065 analogues containing a thiol moiety can be any of the
following A subunits of the formulae A-1 {CPI (Cyclopropyl form)}, A-2
{CPI (Chloromethyl form)), A-3 {CBI (Cyclopropyl form)}, and A-4 {CBI
(Chloromethyl form)} covalently linked via an amide bond from the
secondary amino group of the pyrrole moiety of the A subunit to the C-2
carboxy group of either a B subunit of the formula F-1 or a B-C subunit of the
formulae F-3 or F-7.
A subunits
CH 3 CH 3 C1
NH NH O A-1 OH A-2
NH NH O A-3 OH A-4
B and covalently bound B and C subunits
R7 R6
R4
R3 R R3
HOOC W1 R2 HOOC W R2 0 R4
R1 F-1 R1 F-3
0
N R5
/\ R4 N
HOOC 0 R3
W1 R2
R1 F-7
wherein each Wi and W2 may be the same or different and may
be 0 or NH; and
wherein, in Formula F-1 R 4 is a thiol moiety, in Formula F-3
one of R or R 4 is a thiol moiety, in Formula F-7 one of R' or R4 is a thiol
containing moiety; when R or R' is a thiol moiety, then R, to R 6 , which may
be the same or different, are hydrogen, C1 -C 3 linear alkyl, methoxy, hydroxyl,
primary amino, secondary amino, tertiary amino, or amido; and when R 4 is a
thiol moiety, R, R 1, R2 , R3, R 4, R5 and R6, which may be the same or different,
are hydrogen, Ci -C 3 linear alkyl, methoxy, hydroxyl, primary amino,
secondary amino, tertiary amino, or amido, and R' is NH 2 , alkyl, 0-alkyl,
primary amino, secondary amino, tertiary amino, or amido. In addition, the chlorine atom in A-2 and A-4 subunits can be replaced with another suitable halogen.
[147] In a preferred embodiment, R and R' are thiol moieties and R1
and R2 are each hydrogen. In another preferred embodiment, R and R' are
thiol moieties and R, to R6 are each hydrogen.
[148] In an especially preferred embodiment, R or R 4 is
-NHCO(CH 2)SH, -NHCOC6H 4(CH 2)SH, or -O(CH 2),SH, and R' is
-(CH 2)SH, -NH(CH 2 )SH or -O(CH 2),SH wherein / is an integer of 1 to 10.
[149] Examples of primary amines include methyl amine, ethyl
amine and isopropyl amine.
[150] Examples of secondary amines include dimethyl amine,
diethylamine and ethylpropyl amine.
[151] Examples of tertiary amines include trimethyl amine, triethyl
amine, and ethyl-isopropyl-methyl amine.
[1521 Examples of amido groups include N-methylacetamido,
N-methyl-propionamido, N-acetamido, and N-propionamido.
[153] Examples of alkyl represented by R', when R' is not a linking
group, include CI-C 5 linear or branched alkyl.
[154] Examples of O-alkyl represented by R' when R' is not a linking
group, include compounds where the alkyl moiety is a Ci-C5 linear or
branched alkyl.
[1551 The above-described CC-1065 analogues may be isolated from
natural sources and methods for their preparation, involving subsequent
modification, synthetic preparation, or a combination of both, are well
described (see, e.g., U.S. patent nos. 5,475,092, 5,585,499 and 5,846,545).
Preferred CC-1065 analogs are those described in U.S. Patent Nos. 5,475,092;
5,595,499; 5,846,545; 6,534,660; 6,586,618; 6,756,397 and 7,049,316
Daunorubicin/DoxorubicinAnalogues
[156] The cytotoxic agent according to the present invention may
also be a daunorubicin analogue or a doxorubicin analogue.
[1571 The daunorubicin and doxorubicin analogues of the present
invention can be modified to comprise a thiol moiety.
[158] The modified doxorubicin/daunorubicin analogues useful in the
present invention have the formula D1 shown below:
CH2X
OWe O OH O
CH 3 0
R Y R' D1
wherein,
X is H or OH;
Y is 0 or NR 2, wherein R2 is linear or branched alkyl having 1
to 5 carbon atoms;
R is a thiol moiety, H, or liner or branched alkyl having 1 to 5
carbon atoms; and
R' is a thiol moiety, H, or -OR 1, wherein R, is linear or
branched alkyl having 1 to 5 carbon atoms;
provided that R and R' are not thiol moieties at the same time.
[1591 In a preferred embodiment, NR 2 is NCH 3 . In another preferred
embodiment, R' is -0.
[1601 In an especially preferred embodiment, the thiol moiety is
-(CH 2)nSH, -O(CH 2)nSH, -(CH 2)nCH(CH 3)SH, -O(CH 2)nCH(CH 3)SH,
-(CH 2)nC(CH 3)2 SH, or -O(CH 2)nC(CH 3)2 SH, wherein n is an integer of 0 to
10.
[161] Examples of the linear or branched alkyl having 1 to 5 carbon
atoms, represented by R, R1 , and R2, include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, and pentyl, in any of its
eight isomeric arrangements.
[162] R 1 and R 2 preferably are methyl.
[163] Examples of linear alkyls include methyl, ethyl, propyl, butyl,
pentyl and hexyl.
[164] Examples of branched alkyls include isopropyl, isobutyl,
sec.-butyl, tert.-butyl, isopentyl and 1-ethyl-propyl.
[1651 When either R or R' is not a linking group, the substituent in
that position can be varied until a compound of the desired toxicity is
obtained. High toxicity is defined as having an IC50 towards cultured cancer
cells in the range of 1 x 1042 to 1 x 10 M, upon a 72 hour exposure time.
Representative examples of substituents are H, alkyl, and O-alkyl, as
described above. One of ordinary skill in the art can determine the appropriate
chemical moiety for R and R' using only routine experimentation.
[166] For example, methyl and methoxy substituents are expected to
increase the cytotoxic potency, while a hydrogen is not expected to increase
the potency as compared to the parent daunorubicin analogues with
substituents at the different positions will be initially prepared and evaluated
for in vitro cytotoxicity.
[1671 The modified doxorubicin/daunorubicin analogues of the
present invention, which have a thiol moiety, are described in WO 01/38318.
The modified doxorubicin/daunorubicin analogues can be synthesized
according to known methods (see, e.g., U.S. Patent No. 5,146,064).
[1681 Auristatin include auristatin E, auristatin EB (AEB), auristatin
EFP (AEFP), monomethyl auristatin E (MMAE) and are described in U.S.
Patent No. 5,635,483, Int. J. Oncol. 15:367-72 (1999); Molecular Cancer
Therapeutics, vol. 3, No. 8, pp. 921-932 (2004); U.S. Application Number
11/134826. U.S. Patent Publication Nos. 20060074008, 2006022925.
[1691 The cytotoxic agents according to the present invention include
pyrrolobenzodiazepine dimers that are known in the art (US Patent Nos
7,049,311; 7.067.511; 6,951,853; 7,189,710; 6,884,799; 6,660,856.
Analogues and derivatives
[1701 One skilled in the art of cytotoxic agents will readily
understand that each of the cytotoxic agents described herein can be modified
in such a manner that the resulting compound still retains the specificity and/or
activity of the starting compound. The skilled artisan will also understand that
many of these compounds can be used in place of the cytotoxic agents
described herein. Thus, the cytotoxic agents of the present invention include
analogues and derivatives of the compounds described herein.
Therapeutic Use
[171] The cell-binding agent drug conjugates (e.g.,
immunoconjugates) of this invention can also be used in combination with
other chemotherapeutic agents. Such chemotherapeutic agents are listed
above or are described in U.S. Patent No. 7,303,749.
[172] The cell-binding agent drug conjugates (e.g.,
immunoconjugates) of the present invention can be administered in vitro, in
vivo and/or ex vivo to treat patients and/or to modulate the growth of selected
cell populations including, for example, cancer of the lung, blood, plasma,
breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and
lymphatic organs; autoimmune diseases, such as systemic lupus, rheumatoid
arthritis, and multiple sclerosis; graft rejections, such as renal transplant
rejection, liver transplant rejection, lung transplant rejection, cardiac transplant
rejection, and bone marrow transplant rejection; graft versus host disease; viral
infections, such as CMV infection, HIV infection, and AIDS; and parasite
infections, such as giardiasis, amoebiasis, schistosomiasis, and the like.
Preferably, the immunoconjugates and chemotherapeutic agents of the
invention are administered in vitro, in vivo and/or ex vivo to treat cancer in a
patient and/or to modulate the growth of cancer cells, including, for example,
cancer of the blood, plasma, lung, breast, colon, prostate, kidney, pancreas,
brain, bones, ovary, testes, and lymphatic organs; more preferably lung, colon
prostrate, plasma, blood or colon cancer.
[173] "Modulating the growth of selected cell populations" includes
inhibiting the proliferation of selected cell populations (e.g., multiple myeloma
cell populations, such as MOLP-8 cells, OPM2 cells, H929 cells, and the like)
from dividing to produce more cells; reducing the rate of increase in cell
division as compared, for example, to untreated cells; killing selected cell
populations; and/or preventing selected cell populations (such as cancer cells)
from metastasizing. The growth of selected cell populations can be modulated
in vitro, in vivo or ex vivo.
[174] In the methods of the present invention, the cell-binding agent
drug conjugates (e.g., immunoconjugates) can be administered in vitro, in
vivo, or ex vivo. The cell-binding agent drug conjugates (e.g.,
immunoconjugates) can be used with suitable pharmaceutically acceptable
carriers, diluents, and/or excipients, which are well known, and can be
determined, by one of skill in the art as the clinical situation warrants.
Examples of suitable carriers, diluents and/or excipients include: (1)
Dulbecco's phosphate buffered saline, pH about 6.5, which would contain
about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v
NaCl), and (3) 5% (w/v) dextrose.
[1751 The compounds and compositions described herein may be
administered in appropriate form, preferably parenterally, more preferably
intravenously. For parenteral administration, the compounds or compositions
can be aqueous or nonaqueous sterile solutions, suspensions or emulsions.
Propylene glycol, vegetable oils and injectable organic esters, such as ethyl
oleate, can be used as the solvent or vehicle. The compositions can also
contain adjuvants, emulsifiers or dispersants.
[1761 The compositions can also be in the form of sterile solid
compositions that can be dissolved or dispersed in sterile water or any other
injectable sterile medium.
[177] The "therapeutically effective amount" of the cell-binding agent
drug conjugate (e.g., immunoconjugates) described herein refers to the dosage
regimen for modulating the growth of selected cell populations and/or treating
a patient's disease, and is selected in accordance with a variety of factors,
including the age, weight, sex, diet and medical condition of the patient, the
severity of the disease, the route of administration, and pharmacological
considerations, such as the activity, efficacy, pharmacokinetic and toxicology
profiles of the particular compound used. The "therapeutically effective
amount" can also be determined by reference to standard medical texts, such
as the Physicians Desk Reference 2004. The patient is preferably an animal,
more preferably a mammal, most preferably a human. The patient can be male
or female, and can be an infant, child or adult.
[178] Examples of suitable protocols of cell-binding agent drug
conjugates (e.g., immunoconjugate) administration are as follows. The
conjugates can be given daily for about 5 days either as an i.v., bolus each day
for about 5 days, or as a continuous infusion for about 5 days.
[179] Alternatively, the conjugates can be administered once a week
for six weeks or longer. As another alternative, the conjugates can be
administered once every two or three weeks. Bolus doses are given in about 50
to about 400 ml of normal saline to which about 5 to about 10 ml of human
serum albumin can be added. Continuous infusions are given in about 250 to
about 500 ml of normal saline, to which about 25 to about 50 ml of human
serum albumin can be added, per 24 hour period. Dosages will be about 10 pg
to about 1000 mg/kg per person, i.v. (range of about 100 ng to about 100
mg/kg).
[180] About one to about four weeks after treatment, the patient can
receive a second course of treatment. Specific clinical protocols with regard to
route of administration, excipients, diluents, dosages, and times can be
determined by the skilled artisan as the clinical situation warrants.
[181] The present invention also provides pharmaceutical kits
comprising one or more containers filled with one or more of the ingredients
of the pharmaceutical compounds and/or compositions of the present
invention, including, one or more immunoconjugates and one or more
chemotherapeutic agents. Such kits can also include, for example, other
compounds and/or compositions, a device(s) for administering the compounds
and/or compositions, and written instructions in a form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products.
[182] The compounds and conjugates (e.g., immunoconjugates could
also be used for the manufacture of a medicament useful for treating or
lessening the severity of disorders, such as, characterized by abnormal growth
of cells (e.g., cancer).
[183] Cancer therapies and their dosages, routes of administration
and recommended usage are known in the art and have been described in such
literature as the Physician's Desk Reference (PDR). The PDR discloses
dosages of the agents that have been used in treatment of various cancers. The
dosing regimen and dosages of these aforementioned chemotherapeutic agents
and conjugates that are therapeutically effective will depend on the particular
cancer being treated, the extent of the disease and other factors familiar to the
physician of skill in the art and can be determined by the physician. For
example, the 2006 edition of the Physician's Desk Reference discloses that
Taxotere (see p. 2947) is an inhibitor of tubulin depolymerization;
Doxorubicin (see p 786), Doxil (see p 3302) and oxaliplatin (see p 2908) are
DNA interacting agents, Irinotecal (see p. 2602) is a Topoisomerase I
inhibitor, Erbitux (see p 937) and Tarceva (see p 2470) interact with the
epidermal growth factor receptor. The contents of the PDR are expressly
incorporated herein in their entirety by reference. One of skill in the art can
review the PDR, using one or more of the following parameters, to determine
dosing regimens and dosages of the chemotherapeutic agents and conjugates, which can be used in accordance with the teachings of this invention. These parameters include:
1. Comprehensive index
a) by Manufacturer
b) Products (by company's or trademarked drug name)
c) Category index (for example, "antihistamines", "DNA
alkylating agents" taxanes etc.)
d) Generic/chemical index (non-trademark common drug names)
2. Color images of medications
3. Product information, consistent with FDA labeling
a) Chemical information
b) Function/action
c) Indications & Contraindications
d) Trial research, side effects, warnings
[184] All references cited herein and in the examples that follow are
expressly incorporated by reference in their entireties.
[1851 The invention will now be described by reference to non
limiting examples. Unless otherwise specified, all percents and ratios are by
volume.
Example 1: Materials and Methods
Methyl 2-(acetylthio)-4-bromobutanoate
Br SAc
Br HSAc/DIPEA Br S O1 THF, -20°C-0°C >95% 0
[186] 10.0 g (38.4 mmol) of methyl 2,4-dibromobutanoate in 100 ml
of dry THF at 200 C was added drop wise the mixture of 2.75 ml (38.5 mmol)
of thiolacetic acid in 8.5 ml (48.9 mmol) of DIPEA and 50 ml of dry THF in
1.5 hour. After stirring overnight at -20 0C then 0C for 2 hours under Ar, the
mixture was concentrated, diluted with EtAc/Hexane, washed with 1.0 M
NaH 2PO 4, dried over MgSO 4 , filtered, evaporated, and SiO 2 chromatographic
purification (1:12 to 1:10 EtAc/Hexane) to afford 9.5 g (96%) of the title
compound. 1H NMR (CDC3) 4.38 (1H, t, J = 7.1Hz), 3.74 (s, 3H), 3.40 (m,
2H), 2.57 ~ 2.47 (m, 1H), 2.37 (s, 3H), 2.36 - 2.21 (m, 1H); 13C NMR
193.24, 171.36, 53.15, 44.45, 34.67, 30.46, 29.46; MS m/z+ 276.9 (M+Na),
278.9 (M+2+Na)
4-Bromo-1-methoxy-1-oxobutane-2-sulfonic acid
SAc SO 3H Br 0 Br 0 IN, H 20 2/HOAc 0>90% 0
[187] 9.2 g (36.3 mmol) of methyl 2-(acetylthio)-4-bromobutanoate
in 80 ml of acetic acid was added 40 ml of hydrogen peroxide (35% in water).
The mixture was stirred overnight, then evaporated, diluted with water, neutralized with NaHCO3 , washed with 1:1 Hexane/EtAc. The aqueous solution was evaporated, dissolved in methanol, concentrated, and crystallized with methanol/toluene to afford 8.6 g (90% yield) of the title compound. m.p.
= 288~ 293 (decomp); 1H NMR (D20) 4.12 (dd, 1H, J = 4.8, 9.3 Hz), 3.83 (s,
3H), 3.64 (in, 1H), 3.53 (in, 1H), 2.54 (in, 2H); 13C NMR 172.16, 66.73,
55.66, 33.39, 32.70; MS m/z- 260.8 (M-1).
4-(Acetylthio)-1-methoxy-1-oxobutane-2-sulfonic acid
SO 3 H S3 Br 0 HSAc/DIPEA SO3H Br ~~ DMA, 700 C1W"k
>90%
[1881 5.0 g (19.2 mmol) of 4-bromo-1-methoxy-1-oxobutane-2
sulfonic acid in 100 ml of THF was added 3.0 ml of thioacetic acid and 9.0 ml
of DIPEA in 100 ml of THF. The mixture was stirred overnight then refluxed
at 70°C for 1 hr, evaporated and co-evaporated with 3 x 100 ml of water after
being neutralized to pH 7 with NaHCO 3. The mixture was redissolved in
methanol, filtered through celite, concentrated and purified with SiO 2
chromatography eluted with CH30H/CH 2 Cl2/HCOOH 37.5:250:1 to 50:250:1)
to afford 4.4 g (90% yield) of the title compound. 1H NMR(D20) 3.95 (dd,
1H, J = 4.1, 10.3 Hz), 3.83 (s, 3H), 3.74 (in, 2H), 3.22 (dd, 2H, J = 7.4, 14.9
Hz), 2.39 (s, 3H); 13C NMR 203.88, 172.91, 67.32, 56.17, 29.04, 20.61; MS
m/z- 254.8 (M-H)
4-((5-nitropyridin-2-yl)disulfanyl)-2-sulfobutanoic acid
0 S03 H 1) NaOH SO3H 02 N r_ N 0 2) (SPyNO 2) 2 , S -Is OH 0 pH 7.0 SO 3 H
[1891 3.0 g (11.7 mmol) of 4-(Acetylthio)-1-methoxy-1-oxobutane-2
sulfonic acid in 100 ml of water was added 50 ml of 3 M NaOH. After being
stirred under Ar for 3 h, the mixture was neutralized with 1 M H 2 PO4 to pH
7.2 under Ar. The mixture was added dropwise to the solution of 10.0 g (32.2
mmol) of 1,2-bis(5-nitropyridin-2-yl)disulfane in 200 ml of DMA. After
being stirred for 4 h under Ar, the mixture was concentrated, diluted with
water, filtered, evaporated and purified with C-18 4.0 x 20 cm column eluted
with water/methanol (95:5) to afford 3.1 g (75% yield) of the title compound.
m.p. = 288 ~ 291°C (decomp.) 1H NMR (DMF-d7) 9.29 (d, 1H, J = 2.2 Hz),
8.63 (dd, 1H, J = 2.7, 8.9 Hz), 8.17 (d, 1H, J = 8.9 Hz), 3.73 (t, 1H, J = 7.2
Hz), 3.22 ~ 3.17 (in, 1H), 3.15 ~ 3.10 (in, H), 2.41 - 2.33 (in, 2H); 13C NMR
170.92, 169.10, 146.04, 143.67, 133.65, 120.72, 64.22, 37.82, 29.26; MS m/z
352.8 (M-H).
1-(2,5-dioxopyrrolidin-1-yloxy)-4-((5-nitropyridin-2-yl)disulfanyl)-1
oxobutane-2-sulfonic acid
0 2N 0 0 0 2N S O i S HO-N j S" "'OH------- \ ." SOH EDC/DMA SO3H
[190] 220 mg (0.62 mmol) of 4-((5-nitropyridin-2-yl)disulfanyl)-2
sulfobutanoic acid in 15 DMA was added 130 mg (1.13 mmol) of NHS and
480 mg (2.50 mmol) of EDC. The mixture was stirred under Ar overnight,
evaporated and purified on SiO 2 chromatography eluted with
CH2CH2/CH 3 0H/HCOOH (10000:1000:1 to 10000:1500:1) to afford 227 mg
(82% yield) of the title compound. 1H NMR (DMSO-d6) 9.25 (d, 1H, J= 5.2
Hz), 8.57 (dd, 1H, J = 2.5, 8.9 Hz), 8.04 (t, 1H, J = 8.0 + 8.9 Hz), 3.86 (dd,
1H, J 4.9, 9.7 Hz), 3.13 ~ 3.12 (m, 2H), 2.76 (s, 4H), 2.36 -2.30 (m, 1H),
2.25 2.21 (m, 1H); 13C NMR 166.96, 165.01, 144.93, 142.26, 132.63,
119.61, 61.00, 35.03, 29.30, 25.39; MS m/z- 449.8 (M-H).
Methyl 2-(acetylthio)-4-bromobutanoate
Br SAc
Br O0 HSAc/DIPEA Br 0 THF, -20°C-0°C >95% 0
[1911 10.0 g (38.4 mmol) of methyl 2,4-dibromobutanoate in 100 ml
of dry THF at -20°C was added dropwise the mixture of 2.75 ml (38.5 mmol)
of thiolacetic acid in 8.5 ml (48.9 mmol) of DIPEA and 50 ml of dry THF in
1.5 hour. After stirring overnight at -20 0C then 0C for 2 hours under Ar, the
mixture was concentrated, diluted with EtAc/Hexane, washed with 1.0 M
NaH 2 PO 4, dried over MgSO 4 , filtered, evaporated, and SiO2 chromatographic
purification (1:12 to 1:10 EtAc/Hexane) to afford 9.5 g (96%) of the title
compound. 1H NMR (CDCl3) 4.38 (111, t, J = 7.1Hz), 3.74 (s, 3H), 3.40 (m,
2H), 2.57 ~ 2.47 (m, 1H), 2.37 (s, 3H), 2.36 ~ 2.21 (m, 1H); 13C NMR
193.24, 171.36, 53.15, 44.45, 34.67, 30.46, 29.46; MS m/z+ 276.9 (M+Na),
278.9 (M+2+Na)
4-Bromo-1-methoxy-1-oxobutane-2-sulfonic acid
SAc SO 3H
H 20 2/HOAc Br O Br O1- ' 0 >90% 0
[192] 9.2 g (36.3 mmol) of methyl 2-(acetylthio)-4-bromobutanoate
in 80 ml of acetic acid was added 40 ml of hydrogen peroxide (35% in water).
The mixture was stirred overnight, then evaporated, diluted with water,
neutralized with NaHCO3 , washed with 1:1 Hexane/EtAc. The aqueous
solution was evaporated, dissolved in methanol, concentrated, and crystallized
with methanol/toluene to afford 8.6 g (90% yield) of the title compound. m.p.
= 288~ 293 (decomp); 1H NMR (D20) 4.12 (dd, 1H, J = 4.8, 9.3 Hz), 3.83 (s,
3H), 3.64 (m, 1H), 3.53 (m, 1H), 2.54 (m, 211); 13C NMR 172.16, 66.73,
55.66, 33.39, 32.70; MS m/z- 260.8 (M-1).
4-(Acetylthio)-1-methoxy-1-oxobutane-2-sulfonic acid
SO3 H S3 Br 0 HSAc/DIPEA 0 SO 3H Br k 0 0 DMA, 700C0 >90%
[193] 5.0 g (19.2 mmol) of 4-bromo--methoxy-1-oxobutane-2
sulfonic acid in 100 ml of THF was added 3.0 ml of thioacetic acid and 9.0 ml
of DIPEA in 100 ml of THF. The mixture was stirred overnight then refluxed
at 70C for 1 hr, evaporated and co-evaporated with 3 x 100 ml of water after
neutralized to pH 7 with NaHCO 3 . The mixture was redissolved in methanol,
filtered through celite, concentrated and purified with SiO 2chromatography
eluted with CH30H/CH 2Cl2/HCOOH 37.5:250:1 to 50:250:1) to afford 4.4 g
(90% yield) of the title compound. 1H NMR(D20) 3.95 (dd, 1H, J = 4.1, 10.3
Hz), 3.83 (s, 3H), 3.74 (m, 2H), 3.22 (dd, 2H, J = 7.4, 14.9 Hz), 2.39 (s, 3H);
13C NMR 203.88,172.91, 67.32, 56.17,29.04,20.61; MS m/z- 254.8 (M-H)
4-((5-nitropyridin-2-yl)disulfanyl)-2-sulfobutanoic acid
0 S03H SO3H 1) NaOH 02 N N0 2) (SPYN0 2)2 , 7 OH SO pH 7. SO 3H
[194] 3.0 g (11.7 mmol) of 4-(Acetylthio)-1-methoxy-1-oxobutane-2
sulfonic acid in 100 ml of water was added 50 ml of 3 M NaOH. After stirring
under Ar for 3 h, the mixture was neutralized with 1 M H 2PO4 to pH 7.2 under
Ar. The mixture was added dropwise to the solution of 10.0 g (32.2 mmol) of
1,2-bis(5-nitropyridin-2-yl)disulfane in 200 ml of DMA. After stirring for 4 h under Ar, the mixture was concentrated, diluted with water, filtered, evaporated and purified with C-18 4.0 x 20 cm column eluted with water/methanol (95:5) to afford 3.1 g (75% yield) of the title compound. m.p.
= 288 ~ 291°C (decomp.) 1H NMR (DMF-d7) 9.29 (d, 1H, J = 2.2 Hz), 8.63
(dd, 1H, J = 2.7, 8.9 Hz), 8.17 (d, 1H, J = 8.9 Hz), 3.73 (t, 1H, J = 7.2 Hz),
3.22 - 3.17 (in, 1H), 3.15 ~ 3.10 (in, 1H), 2.41 - 2.33 (in, 2H); 13C NMR
170.92, 169.10, 146.04, 143.67, 133.65, 120.72, 64.22, 37.82, 29.26; MS m/z
352.8 (M-H).
1-(2,5-dioxopyrrolidin-1-yloxy)-4-((5-nitropyridin-2-yl)disulfanyl)-1
oxobutane-2-sulfonic acid
02 N N H 0 2N N
OH--------- \I 0 SOH EDC/DMA SO 3 H
[1951 220 mg (0.62 mmol) of 4-((5-nitropyridin-2-yl)disulfanyl)-2
sulfobutanoic acid in 15 DMA was added 130 mg (1.13 mmol) of NHS and
480 mg (2.50 mmol) of EDC. The mixture was stirred under Ar overnight,
evaporated and purified on SiO 2 chromatography eluted with
CH2 CH2/CH 30H/HCOOH (10000:1000:1 to 10000:1500:1) to afford 227 mg
(82% yield) of the title compound. 1H NMR (DMSO-d6) 9.25 (d, 1H, J = 5.2
Hz), 8.57 (dd, 1H, J = 2.5, 8.9 Hz), 8.04 (t, 1H, J = 8.0 + 8.9 Hz), 3.86 (dd,
1H, J = 4.9, 9.7 Hz), 3.13 ~ 3.12 (in, 2H), 2.76 (s, 4H), 2.36 -2.30 (in, 1H),
2.25 ~ 2.21 (m, 1H); 13C NMR 166.96, 165.01, 144.93, 142.26, 132.63,
119.61, 61.00, 35.03, 29.30, 25.39; MS m/z- 449.8 (M-H).
4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid
SO 3H
2)PySSPy, S OH 0 pH 7.0 SO 3 H
[1961 1.5 g (5.85 mmol) of 4-(Acetylthio)-1-methoxy--oxobutane-2
sulfonic acid was added to 100 ml of 0.5 M NaOH solution. After stirring
under Ar for 3 h, the mixture was concentrated to- 50 ml and neutralized with
1 M H 2 PO4 to pH 7.2 under Ar. The mixture was added dropwise to the
solution of 4.0 g (18.1 mmol) of 2,2'-dithiodipyridine in 60 ml of DMA. After
stirring for 4 h under Ar, the mixture was concentrated, diluted with water,
filtered, evaporated and purified with C-18 4.0 x 20 cm column eluted with
water/methanol (99:1 to 90:10) to afford 1.32 g (73% yield) of the title
compound. 1H NMR (DMF-d7) 8.39 (dd, 1H, J = 3.5, 4.8 Hz), 7.86 (m, 2H),
7.25 (m, 1H), 3.59 (dd, 1H, J = 5.2, 9.4 Hz), 2.90 (m, 2H), 2.28 (m, 2H); 13C
NMR 172.60, 159.16, 148.93, 138.09, 121.03, 119.38, 67.49, 36.39, 28.666;
MS m/z- 307.8 (M-H).
1-(2,5-dioxopyrrolidin-1-yloxy)-1-oxo-4-(pyridin-2-yldisulfanyl)butane-2
sulfonic acid f HO-N a_ 0-N0 S OH - -- O-N SO 3 H EDC/DMA SO 3 H
[1971 680 mg (2.20 mmol) of 4-(pyridin-2-yldisulfanyl)-2
sulfobutanoic acid in 50 DMA was added 300 mg (2.60 mmol) of NHS and
800 mg (4.16 mmol) of EDC. The mixture was stirred under Ar overnight,
evaporated and purified on SiO 2 chromatography eluted with
CH2 CH2/CH 30H/HCOOH (10000:1000:1 to 10000:1500:1) to afford 720 mg
(80% yield) of the title compound. 1H NMR (DMSO-d6) 8.40 (dd, 1H, J =
3.5, 4.7 Hz), 7.85 (in, 2H), 7.24 (in, 1H), 3.58 (dd, 1H, J= 5.1, 9.4 Hz), 2.94 ~
2.90 (in, 2H), 2.74 (s, 4H), 2.31 ~2.27 (in,2H); 13C NMR 168.16, 161.11,
147.91, 139.22, 121.63, 119.31, 66.80, 36.30, 28.36, 25.42; MS m/z- 404.9
3, 6-endoxo-A-tetrahydrophthalhide
NH 0\ /- 0NH 0 00
[198] Maleimide (5.0 g, 51.5 mmol) in ethylether (200 ml) was added
furan (5.5 ml, 75.6 mmol). The mixture was heated inside a 1 L of autoclave
bomb at 100 0C for 8 h. The bomb was cooled down to room temperature, and
the inside solid was rinsed with methanol, concentrated and crystallized in
ethyl acetate/hexane to afford 8.4 g (99%) of the title compound. 1H NMR
(DMF-d7):11.08 (s, 1H) (NH), 6.60 (in, 2H), 5.16 (in, 2H), 2.95 (in, 2H). 13C
NMR 178.84,137.69, 82.00, 49.92. MS m/z+ 188.4 (MW + Na).
Methyl 4-N-(3, 6-endoxo-A-tetrahydrophthalido)-2-sulfo-butyrate
~I\-k O1 O O0 K2CO,/KI/DMF
o Br S03H
[199] 3, 6-Endoxo-A-tetrahydrophthalhide (0.80 g, 4.85 mmol) in
DMA (20 ml) was added K2 C03 (1.4 g, 10.13 mmol) and KI (0.19 g, 1.14
mmol). After stirring under Ar for 1 hr, methyl 4-bromo-2-sulfo-butyrate (0.98
g, 3.77 mmol) in DMA (10 ml) was added. The mixture was stirred under Ar
overnight, evaporated, re-dissolved in 1% HAc in methanol, filtered,
evaporated and purified by SiO 2 chromatography and eluted with 1:5:0.01 to
1:4:0.01 CH 30H/CH 2Cl2/HAc to afford 0.98 (75%) g of the title compound.
1H NMR (DMF-d7): 6.59 (in, 2H), 5.16 (dd, 2H, J = 0.8, 7.8 Hz), 3.65-3.63
(in, 3H), 3.47 (in, 2H), 3.01 (s, 3H), 2.83 (in,2H). 13C NMR 172.94,162.86,
137.68, 81.98, 52.39, 49.91, 48.58, 36.01, 21.97. MS m/z- 343.9 (MW - H).
Methyl 4-N-maleimido-2-sulfo-butyrate
0 2 o 0 0 - N ~~ O Reflux <KN O O SO3 H o SO 3H
[200] In an opened round bottom flask, methyl 4-N-(3, 6-endoxo-A
tetrahydrophthalido)-2-sulfo-butyrate (0.30 g, 0.87 mmol) in 20 ml of 1:1
DMA/ 100 mM NaH 2 PO 4 , pH 7.0 was heated at 120 - 140°C for 4 h. During
the reaction time, 5 x 10 ml of water was gradually added to keep the reaction
volume around 15 ml. The mixture was concentrated to dryness and purified
by SiO 2 chromatography eluted with 1:5:0.01 to 1:4:0.01
CH3 0H/CH 2C 2/HAc to afford 0.230 g (95%) of the title compound. 'H NMR
(DMF-d7): 6.60 (s, 2H), 4.06 (d, 1H), 3.60 (m, 3H), 3.47 (m, 2H), 2.43 (m,
2H); 13 C NMR 171.59, 164.96, 136.10, 66.20, 51.71, 34.82, 22.10. MS m/z
276.6 (MW - H).
Methyl 4-azido-2-sulfo-butyrate
0 0 Br NaN3 , N3 S0 3H DMA, >90% S0 3H
[201] Methyl 4-bromo-2-sulfo-butyrate (1.07 g, 4.11 mmol) and
sodium azide (0.70 g (10.7 mmol) in DMF (50 ml) was stirred overnight. The
mixture was evaporated and purified by SiO 2 chromatography and eluted with
1:5:0.01 CH30H/CH 2 C 2/HAc and crystallized with CH3 0H/Toluene/Hexane
to afford 1.00 g (95%) of the title compound. m.p = 267 -272 C (decomp). 1H
NMR (DMF-d7): 12.06 (br, 1H), 3.65 (s, 3H), 3.59 (dd, 1H, J = 5.4, 8.9 Hz), 3 C NMR 171.10, 64.29, 52.24, 50.64, 21.35. ESI 3.47 (m, 2H), 2.24 (m, 2H).
MS m/z+ 267.9 (M + 2Na-H), m/z- 222.0 (M-H). HRMS m/z- (C 5H9 N 305 S
H) called 222.0185, found 222.0179.
4-azido-2-sulfo-butyric acid
0 0 N3 MHCI 0 N3 OH HAc,1I00C SO 3H >95% SO 3H
[202] Methyl 4-azido-2-sulfo-butyrate (1.00 g, 4.08 mmol) in the
mixture of HCl (50 ml, 1.0 M) and HAC (5 ml) was heated at 100°C for 8 hrs.
The mixture was evaporated and co-evaporated 3x 50 ml of water, and
crystallized with water/acetone to afford 1.0 g (99%) of the title compound. 'H
3 C NMR 170.96, NMR (DMF-d 7): 3.60 (m, 2H), 3.52 (m, 1H), 2.24 (m, 2H).
63.04, 50.66, 29.12. ESI MS m/z- 207.7 (MW -H); HRMS m/z- (C 4H 7N 30 5 S
H) calcd 208.0028, found 208.0021.
4-Amino-2-sulfo-butyric acid
0 0 N3 OH H2/Pd/C , H2N OH S0 3H H2 0, >95% SO 3H
[203] 4-Azido-2-sulfo-butyric acid (500 mg, 2.40 mmol), water (20
ml) and Pd/C (110 mg, 10% Pd, 50% water based) were placed into a 250 ml
hydrogenation shaking bottle. After the air in the bottle was sucked out by a
vacuum, 20 psi of hydrogen was let into the bottle. The mixture was shaken
for 8 h, then filtered through celite, washed with DMF, evaporated and co
evaporated with dry DMF to afford 476 mg (91% HCI salt) of the title
product. ESI MS m/z- 181.8 (MW -H). This product was used directly without
further purification.
(Z)-4-(3-carboxy-3-sulfopropylamino)-4-oxobut-2-enoic acid
000 0
H 2N OH H OH SO 3 H DMF, >90% O SO 3 H
[204] The above 4-Amino-2-sulfo-butyric acid, HCl salt (476 mg,
2.16 mmol) in dry DMF (20 ml) was added maleic anhydride (232 mg, 2.36
mmol). The mixture was stirred under Ar overnight, evaporated and purified
on self packed c-18, 41.0 x 25 cm column, eluted with water. The fractions contained product were pooled, evaporated and crystallized with H 20/acetone to afford 552 mg (91%) of the title product. 'H NMR (DMF-d7): 9.70 (br,
1H), 6.73 (d, 1H, J = 12.8 Hz), 6.32 (d, 1H, J = 12.8 Hz), 3.69 (m, 1H), 3.47
(m, 2H), 2.27 (m, 2H). 13 C NMR 171.47, 167.32, 165.87, 135.44, 133.07,
63.82, 39.13, 27.62. ESI MS m/z- 279.8 (MW -H); HRMS m/z- (CsHiNOsS
H) calcd 280.0127, found 280.0121.
4-N-Maleimido-2-sulfo-butanoic acid
40 0 0 o 1). HMDS/ZnCI/DMA N OH
>85% O
[2051 (Z)-4-(3-carboxy-3-sulfopropylamino)-4-oxobut-2-enoic acid
(310 mg, 1.10 mmol) in mixture dry DMA (5 ml) and dry toluene (20 ml) was
heated. After the temperature reached at 80°C, HMDS (hexamethyldisilazane)
(1.40 ml, 6.71 mmol) and ZnC12 (1.85 ml, 1.0 M in diethyl ether, 1.85 mmol)
was added. The mixture was continued heated to 115 ~ 125°C and toluene was
collected through Dean-Stark trap. The reaction mixture was fluxed at 120 °C
for 6 h. During this period, 2 x 20 ml of dry toluene was added to keep the
mixture volume around 8 - 10 ml. Then the mixture was cooled, 1 ml of 1:10
HCl (conc)/CH 30H was added, evaporated, purified on Si02 chromatography
eluted with CH 30H/CH 2 C 2 /HAc (1:5:0.01 to 1:4:0.01) to afford 260mg
(92%) of the title product. 'H NMR (DMF-d 7): 10.83(br, 1H), 6.95 (s, 2H) ,
13C iH, J= 12.8 Hz), 3.65 (in, 1H), 3.54 (in, 2H), 2.27 (in, 2H). NMR 173.61,
172.04, 135.47, 64.18, 37.1, 27.89. ESI MS m/z- 261.8 (MW -H). HRMS m/z
(C8H 9NO7 S -H) called 262.0021, found 262.0027.
Succinimidyl4-N-maleimido-2-sulfo-butyrate 0 ~00 0 HO-N10 OH
O SO 3H EDC/DMA O SO3 H o
[206] 4-N-maleimido-2-sulfo-butanoic acid (260 mg, 0.99 mmol) in
DMA (10 ml) was added to NHS (220 mg, 1.91 mmol) and EDC (500 mg,
2.60 mmol). The mixture was stirred under Ar overnight, evaporated and
purified on SiO 2 chromatography eluted with CH 2CH 2/CH 3 0H/HAc
(10000:1000:1 to 10000:2000:1), then crystallized with DMA/EtAc/Hexane to
afford 285 mg (81% yield) of the title compound. 'H NMR (DMF-d7) 6.99 (s,
1H), 3.83 (in, 1H), 3.64 (in, 2H), 2.75 (s, 4H), 2.34 (in, 2H); "C NMR 171.97,
171.82, 166.64, 135.58, 62.00, 36.66, 26.62; ESI MS m/z- 358.9 (M-H);
HRMS m/z- (C1 2H1 2N 2 0 9 S -H) calcd 359.0185, found 359.0178
(E)-Methyl4-azidobut-2-enoate
0 0 BrO/) 3 N3 O
[207] To the solution of NaN 3 (2.80 g, 43.01 mmol) in 100 ml of
DMF at -200 C was added methyl 4-bromocrotonate (5.00 ml, 85%, 36.10 mmol). After stirred at -20°C for 30 min, the mixture was stirred at 0C for 4 h, evaporated, suspended with EtAc/Hexane (1:1), filtered, evaporated and chromatographic purification on SiO2 column eluted with EtAc/Hexane (1:25 to 1: 10 ) to afford HRMS for 4.08 g (80%) of the title product. 'H NMR
(CDCl3) 6.88 (m, 1H), 6.06 (ddd, 1H, J -= 1.7, 3.4, 15.6 Hz), 3.97 (dd, 2H, J =
1.2, 4.96 Hz), 3.73 (s, 3H); 1 3 C NMR 166.23, 140.86, 123.49, 51.95, 51.36;
ESI MS m/z+ 182.5 (M+ Na + H2 0); HRMS m/z+ (C5 H 7N 3 0 2 + H2 0 + Na)
called 182.0542, found 182.0548.
Methyl 3-(acetylthio)-4-azidobutanoate
0 SAc O N3 0 P N3 O
[2081 To the solution of (E)-Methyl 4-azidobut-2-enoate (4.00g,
28.37 mmol) in 60 ml of THF at0C was added the mixture of thiolacetic acid
(3.0 ml, 42.09 mmol) and DIPEA (8.0 ml, 45.92 mmol) in 60 ml of THF in 20
min. After stirred at 0C for 1 hr, the mixture was stirred at RT overnight,
evaporated, redissolved in CH2 C1 2 , washed with NaHCO3 (sat.) and 1 M
NaH 2PO 4/NaCl (sat.), pH 4 respectively, dried over MgSO4, filtered,
evaporated and chromatographic purification on SiO 2 column eluted with
EtAc/Hexane (1:8 to 1: 4) to afford HRMS for 4.98 g (81%) of the title
product. H NMR (CDCl 3) 3.66 (m, 1H), 3.62 (s, 3H), 3.40 (dd, 1H, J = 7.5, 3 C NMR 12.7 Hz), 3.31 (m, 1H), 2.78 (m, 1H), 2.60 (m, 1H), 2.32 (s, 3H);
(DMF-d7) 192.20, 172.48, 56.56, 53.60, 51.31, 34.58, 30.56; ESI MS m/z+
240.0 (M+ Na), 255.9 (M+ K); HRMS m/z+ (C 7HIN 30 3 S+ Na) calcd
240.0419, found 240.0415.
Azido-4-methoxy-4-oxobutane-2-sulfonic acid
SAc 0 SO3H O N3 O/K - N3 0
[209] Methyl 3-(acetylthio)-4-azidobutanoate (4.00 g, 18.43 mmol) in
75 ml of acetic acid was added 25 ml of H202 (30%). The mixture was stirred
overnight, evaporated and co-evaporated with EtOH/toluene and purified on
SiO 2 chromatography eluted with CH 30H/CH 2Cl 2/HAc (100:800:1 to
100:500:1) to afford 3.85 (93%) g the title compound. 'H NMR (CD 30D) 3.78
(dd, 1H, J = 5.0, 12.7 Hz), 3.62 (s, 3H), 3.44 (dd, 1H, J = 7.5, 12.7 Hz), 3.33
(m, 1H), 2.84 (dd, 1H, J = 5.6, 16.5 Hz), 2.57 (dd, 1H, J = 7.5, 16.5 Hz); "C
NMR (DMF-d7) 173.37, 57.31, 52.54, 52.49, 34.51; ESI MS m/z- 221.7 (M+
4-Azido-3-sulfobutanoic acid
SO 3H 0 SO3H O N 3 -Of N3 N K2 0 OH
[2101 Azido-4-methoxy-4-oxobutane-2-sulfonic acid (3.80 g, 17.04
mmol) in 150 ml of 1.0 M HC was added 8.0 ml of HAc. The mixture was
refluxed at 120°C overnight, evaporated and co-evaporated with water, EtOH,
EtOH/toluene respectively and purified on SiO 2 chromatography eluted with
CH3 0H/CH 2C 2/HAc(100:500:1 to 100:400:1) to afford 3.02 (85%) g the title
compound. 'H NMR (CD 3 0D) 3.77 (dd, 1H, J= 5.1, 12.8 Hz), 3.45 (dd, 1H, J
= 7.0, 12.8 Hz), 3.31 (in, 1H), 2.86 (dd, 1H, J = 4.7, 16.7 Hz), 2.51 (dd, 1H, J
= 8.4, 16.7 Hz); 13C NMR (DMF-d7) 173.98, 67.50, 59.78, 27.82; ESI MS
m/z- 207.7 (M -H).
4-amino-3-sulfobutanoic acid
SO 3H O SO3 H O N3 OH H 2N OH
[211] In a 500 ml of hydrogenation bottle was added 4-azido-3
sulfobutanoic acid (3.00 g, 14.35 mmol), 150 ml of methanol and 0.32 g of
Pd/C (10% Pd, 50% wet). After sucked out air, 30 psi of H2 was conducted,
and the mixture was shaken overnight, filtered through celite, evaporated, and
coevaporated with dry EtOH to afford about 2.50 g (95%) of 4-amino-3
sulfobutanoic acid. 'H NMR (CD 3 0D) 3.24 (in, 1H), 3.17 (in, 1H), 2.90 (dd,
1H, J = 2.6, 16.5 Hz), 2.33 (dd, 1H, J = 10.1, 16.5 Hz), ESI MS m/z- 181.60
(M-H). The resulted compound was unstable and was used directly without
further purification.
(Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid
H2N 11 OH O O,
HO 3S OH
[212] To the solution of 4-amino-3-sulfobutanoic acid (~ 2.50 g,
13.66 mmol) in 100 ml of DMA was added maleic anhydride (1.48 g, 15.10
mmol) and the mixture was stirred over night, evaporated, purified on C-18
column (2 x 30 cm) eluted with 1% HAc in water and crystallized with
MeOH/Acetone/toluene to afford 3.34 g (83%) of (Z)-4-(3-carboxy-2
sulfopropylamino)-4-oxobut-2-enoic acid. H NMR (CD 30D) 6.33 (d, 1H, J =
12.6 Hz), 6.10 (d, 1H, J = 12.6 Hz), 3.64 (dd, 1H, J = 5.8, 14.0 Hz), 3.54 (in,
1H), 3.30 (in, 1H), 2.78 (dd, 1H, J = 4.9, 16.8 Hz), 2.39 (in, 1H); "C NMR
173.52, 168.68, 167.98, 135.59, 127.79, 57.31, 40.56, 34.52; ESI MS m/z
279.7 (M -H).
4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-sulfobutanoicacid
00
CHOH 0 0I O 0 IH HO 3S OH HO 3S OH
[2131 (Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid
(450 mg, 1.60 mmol) in mixture of 10 ml of dry DMA and 50 ml of dry
toluene was heated. After the temperature reached at 80°C, HMDS
(hexamethyldisilazane, 1.80 ml, 8.63 mmol, ) and ZnCl2 (3.2 ml, 1.0 M in
diethyl ether) were added. The mixture was continued heated to 115 ~ 125 °C and toluene was collected through Dean-Stark trap. The reaction mixture was fluxed at 120 C for 6 h. During this period, 2 x 20 ml of dry toluene was added to keep the mixture volume around 8 - 10 ml. Then the mixture was cooled, 1 ml of 1:10 HC (conc)/CH 3 0H was added, evaporated, purified on
Si02 chromatography eluted with 1:5:0.01 CH30H/CH 2Cl2/HAc to afford 315
mg (75%) of the title product. 1 H NMR (DMF-d7) 6.96 (s, 2H), 4.04 (dd, 1H,
J = 4.3, 13.8 Hz), 3.47 (m, 1H), 3.23 (dd, 1H, J = 7.4, 14.7Hz), 2.99 (dd, 1H, J
= 3.3 , 16.8 Hz), 2.35 (dd, 1H, J = 8.1, 16.9 Hz); 1 3 C NMR 173.58, 172.18,
135.54, 54.61, 40.24, 32.43, ESI MS m/z- 261.70 (M -H).
1-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-(2,5-dioxopyrrolidin-1-yloxy)
4-oxobutane-2-sulfonicacid
CI,0 01< t
0 O HO 3S OH HO3S ONHS
[214] 4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-sulfobutanoic acid
(110 mg, 0.418 mmol), EDC (240 mg, 1.25 mmol) and N-hydroxysuccinimide
(58 mg, 0.504 mmol) was stirred in 10 ml of DMA for overnight, evaporated
and purified on Si2 chromatography eluted with CH30H/CH 2 C 2/HAc
(100:900:1 to 100: 600:1) to afford 112 mg (75%) of the title product. 1H
NMR (DMF-d7) 6.93 (s, 2H), 4.06 (dd, 1H, J = 4.8, 13.1 Hz), 3.80 (dd, 1H, J
10.7, 13.9 Hz), 3.35 (dd, 1H J= 3.3, 17.8 Hz), 3.25 (in, 1H), 3.10 (dd, 1H, J
3C NMR 172.27, 170.88, 169.29, 135.55, = 2.2, 16.4 Hz), 2.87 (in, 4H);
55.28, 40.22, 32.69, 26.66; ESI MS m/z- 261.70 (M -H).
Ethyl 3-(acetylthio)-3-cyanopropanoate
CN 0 HSAc/Et3N CN 0
THF, O*C, 65%
[2151 (Z)-ethyl 3-cyanoacrylate (5.01 g, 40.00 mmol) in 80 ml of
THF at -20°C was added the solution of thiol acetic acid (5.0 ml, 70.15 mmol)
and DIPEA (16.0 ml, 92.03 mmol) in 20 ml of THF in 30 min. The reaction
was kept at -20°C for 4 hr then room temperature overnight. The mixture was
concentrated, diluted with CH2 C1 2 , washed with saturated NaHCO 3, dried over
MgSO4 , filtered, evaporated and purified by SiO 2 chromatography (1:4
EtAC/Hexane) to afford 5.22 g (65%) of the title compound. Rf =0.25 (1:4
EtAC/Hexane); 'H NMR (CDCl 3), 4.44 (in, 1H), 4.11 (dd, 2H, J = 7.1, 14.3 3 C Hz), 3.38 (in, 1H), 3.15 (in, 1H), 2.17 (s, 3H), 1.19 (t, 3H, J = 7.2 Hz);
NMR 194.12, 173.21, 119.82, 61.35, 33.52, 30.08, 14.62; MS m/z+ 225.9
(MW + Na), m/z- 201.7 (MW-H).
Cyano-3-ethoxy-3-oxopropane-1-sulfonic acid
CN 0 CN 0 AcSk k OSHO3 O
[2161 Ethyl 3-(acetylthio)-3-cyanopropanoate (2.00g, 9.95 mmol) in
acetic acid (40 ml) was added H2 02 (12 ml, 30%). The mixture was stirred overnight, evaporated and purified on silica gel chromatography eluted with methanol/dichloromethane/acetic acid (1:8:0.01 to 1:5:0.01) to afford 1.72 g
(84%) of the title compound. 1H NMR (DMSO), 4.63 (in, 1H), 4.12 (dd, 2H, J
= 7.1, 14.3 Hz), 3.27 (in, 1H), 3.05 (in, 1H), 1.28 (t, 3H, J= 7.2 Hz); "C NMR
173.15, 113.85, 61.38, 48.32, 26.33, 14.15; MS m/z- 205.7 (MW-H).
1-(tert-Butoxycarbonylamino)-4-ethoxy-4-oxobutane-2-sulfonicacid
CN 0 BOC-HN
HO3S O HO 3S OC 2 H5
12171 In a hydrogenation bottle was added Cyano-3-ethoxy-3
oxopropane-1-sulfonic acid (2.50 g, 12.06 mmol), ethanol (80 ml), fresh
filtered Raney Nickel (0.40 g) and BOC anhydride (3.30 g, 15.12 mmol).
After the air inside the bottle was sucked out by vacuum, 20 psi of hydrogen
was conducted to the bottle. The bottle was shaken over night, filtered through
celite, evaporated, and purified on silica gel chromatography eluted with
methanol/dichloromethane/acetic acid (1:6:0.01) to afford 3.18 g (85%) of the
title compound. 1H NMR (DMSO), 6.82 (s, 1H), 4.26 (m, 1H), 4.11 (dd, 2H, J
= 7.1, 14.3 Hz), 3.53 (dd, 1H, J = 4.2, 13.4 Hz), 3.36 (in, 1H), 2.86 (in, 1H),
2.51 (in, 1H), 1.38 (s, 9H), 1.22 (t, 3H, J = 7.2 Hz); 13 C NMR 173.35,155.72,
80.44, 62.05, 52.55, 41.61, 34.50, 28.85, 14.52; MS m/z- 309.8 (MW-H).
4-(tert-butoxycarbonylamino)-3-sulfobutanoic acid
HO 3S OC 2H O HO 3S OH
2
[218] 1-(tert-Butoxycarbonylamino)-4-ethoxy-4-oxobutane-
sulfonic acid (402 mg, 1.29 mmol) in the mixture of THF/H2 0 (1:2, 60 ml)
was added lithium hydroxide monohydrate (2.0 g, 47.6 mmol). The mixture
was stirred under Ar overnight, concentrated, purified on C-18 column (2 x 30
cm) eluted with from 100% water to 10% methanol in water to afford 328 mg
(90%) of the title compound. 'H NMR (DMSO), 6.78 (s, 1H), 4.03 (in, 1H),
3.57 (dd, 1H, J= 4.2,13.4 Hz), 3.41 (in, 1H), 2.89 (in, 1H), 2.61 (in, 1H), 1.39
(s, 9H); "C NMR 174.21, 155.82, 79.85, 59.95, 42.06, 32.52, 28.88, 14.55;
ESI MS 281.8 (M-H);
(Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid
SO 3 H0O BOC-HN O S1OH HO 3S OH 28 0
[219] 4-(Tert-butoxycarbonylamino)-3-sulfobutanoic acid (321 mg,
1.13 mmol) was stirred in the mixture of HCl (conc)/Dioxane (1:4, 15 ml) for
30 min, evaporated and coevaporated with EtOH/Toluene (1:1, 4 x 20 ml) to
dryness. To the dryness material was added maleic anhydride (121 mg, 1.23
mmol) and DMA (20 ml) and the mixture was stirred overnight, evaporated
and run through C-18 column eluted with water and crystallized with
EtOH/Hexane to afford 263 mg (83%) of the title compound. ESI MS 279.8
(M- H). The NMR data are the same through the route with 4-azido-3
sulfobutanoic acid.
N,N,N-trimethyl-2-oxotetrahydrothiophen-3-aminium
0 HCI*H 2 N s CH 3 1
[220] 3-aminodihydrothiophen-2(3H)-one hydrochloride (6.00 g,
39.1 mmol), sodium bicarbonate (3.28 g, 39.1 mmol) and iodomethane (13
mL, 209 mmol) were stirred in dry methanol (100 ml) overnight, filtered
through celite, evaporated, purified on SiO2 column eluted with
MeOH/CH 2 Cl2/HAc(1:5:0.01), and crystallized with EtOH/Hexane to afford
5.25 g (84%) of the title product. mp 228- 231°C. 'H NMR (CD 30D) 4.27 (m,
1H), 3.25 (s, 9H), 2.56 - 2.47 (m, 2H), 2.34 (m, 1H), 2.26 (m, 1H); 13 C NMR
168.97, 75.06, 53.25, 30.85, 16.46; ESI MS m/z+ 160.0 (M+).
1-carboxy-N,N,N-trimethyl-3-(pyridin-2-yldisulfanyl)propan-l-aminium H 3C H 3C 0 H3 CH 3 I YS' H3-N1).NaOH HCN H3HOC-CS S COOH 2). PySSPy, pH7
[2211 N,N,N-trimethyl-2-oxotetrahydrothiophen-3-aminium acetate
(2 g, 9.13 mmol) was stirred in 75 ml of 1 M NaOH (3 g NaOH in 75 ml H2 0)
for 45 min. neutralized with 4 M H3 PO4 to pH 7.4, concentrated, added to 1,2 di(pyridin-2-yl)disulfane (11 g, 49.9 mmol) in 200 ml of MeOH. The mixture was stirred over night, extracted with EtAc. The aqueous solution was evaporated, suspended with MeOH, filtered salt, evaporated and purified on
C-18 column (2 cm x 30 cm) eluted with water/methanol (100 water to 20%
methanol/water) to afford 2.6 g (75%) of the title product. ESI MS m/z+ 309.1
(M +Na-H).
1. Modification of antibody with sulfo linker
[222] The huC242 is modified with sulfo linker at 8 mg/mL antibody,
a 15 fold molar excess of sulfo linker (~30mM stock solution in DMA). The
reaction is carried out in 100 mM NaPi, pH8.0 buffer with DMA (5% v/v) for
15, 30, 120, and 200 minutes at 25 °C. The modified huC242 was purified by
G25 column with 50 mM NaPi, 50 mM NaCl, and 2 mM EDTA, pH6.5 to
remove the excess sulfo linker.
2. Measurement of releasable Spy-NO 2 and antibody concentration of
modified huC242
[223] The assay and spectral measurement were carried in 100 mM
NaPi, pH7.5 at room temperature. The molar ratio of Spy-NO 2 released per
mole of huC242 antibody was calculated by measuring the A 28 0 of the sample
and then the increase in the A394 of the sample after adding DTT (50 pL of 1
M DTT/mL of sample). The concentration of DTT-released 2
mercaptopyridine is calculated using a 6394 nm of 14,205 M'cm'. The concentration of antibody can then be calculated using a 280 nmof 217,560 M
Icm~1 after subtracting the contribution of Spy-NO 2 absorbance at 280 nm
(A394 nm post DTT x 3344/14205) from the total A 28 0 nm measured before DTT
addition. The molar ratio of Spy-N0 2 :Ab can then be calculated. The mg/mL
(g/L) concentration of huC242 is calculated using a molecular weight of
147,000 g/mole.
3. Conjugation reaction
[224] The modified huC242 was reacted with a 1.7-fold molar excess
of DM4 (based on DM4 stock SH concentration) over Spy-NO 2 . The reaction
is carried out at 2.5 mg/mL antibody in 50 mM NaPi, 50 mM NaCl, 2 mM
EDTA, pH6.5 and DMA (5% v/v). After addition of DM4, the reaction was
incubated 25°C for ~20 hours. The final conjugate was purified by G25
column with 10 mM Histidine, 130 mM Glycine, 5% sucrose, pH5.5 to
remove the excess DM4 drug.
4. Calculation of huC242 and DM4 concentration
[2251 The huC242 and DM4 both absorb at the two wavelengths used
to measure each component separately, i.e., 280 and 252 nm. The extinction
coefficient at 280 nm for huC242 is 217,560 and for DM4 is 5180 M-1. The
252 nm/280 nm absorbance ratios of huC242 and DM4 are 0.368 and 5.05
respectively. The concentrations were calculated with following equation
CD= A,, - 0.368Ao 80 CAb= A28 - 5180Cn
24692.4 217,560
Results
Modification L/A D/A Monomer ratio Free drug
% time 15 min 5.0 4.1 96.7% N/D* 30 min 6.1 5.4 96.2% <1% 120 min 6.6 6.8 95.7% <1% 200 min 1 6.6 6.3 95.9% | <1%
C242-Sulfo-DM4 linker titration
Linker DM4 mg/mL ptg/mL Free Excess L:A xs D:A Ab DM4 %Monomer Drug 5 2.4 1.7 1.9 0.83 8.2 95 0 10 4.1 1.7 3.3 0.83 14.4 94 0 15 5.6 1.7 4.6 0.82 20.0 93 0 20 7.3 1.7 6.0 0.82 25.8 91 0 25 9.1 1.3 6.6 0.79 27.7 92 0.6 30 10.4 1.3 7.6 0.68 27.5 94 1.1 35 12.2 1.3 8.2 0.67 26.7 95 1.6
Conjugationprotocol:
[226] Modification was done at pH 8.0, buffer A and 5% DMA for 90
min at room temperature, the antibody concentration is 7 mg/ml. The
modificed antibody was purified by NAP column using Buffer A pH6.5. The
conjugation was down at Buffer A, pH6.5 with 5-10% DMA at room
temperature overnight. The drug to linker ratio ranged from 1.3 to 1.7
deepening on the total drug added.
Example 2: Conjugate Synthesis.
[2271 SPP or SSNPP linker was dissolved in ethanol at a
concentration of approximately 10 mM. Antibody was dialyzed into buffer A
(50 mM KPi, 50 mM NaCl, 2 mM EDTA, pH 6.5). For the linker reaction, the
antibody was at 8 mg/ml, and 7 equivalents of linker were added while stirring
in the presence of 5% (v/v) ethanol. The reaction was allowed to proceed at
ambient temperature for 90 minutes. Unreacted linker was removed from the
antibody by Sephadex G25 gel filtration using a Sephadex G25 column
equilibrated with Buffer A at pH 6.5 or 150 mM potassium phosphate buffer
containing 100 mM NaCl, pH 7.4 as indicated. For the SPP linker, the extent
of modification was assessed by release of pyridine-2-thione using 50 mM
DTT and measuring the absorbance at 343 nm as described below (6343 =
8080 M~ 1 cm1 for free pyridine-2-thione). For SSNPP, modification was
assessed directly by measuring the absorbance at 325 nm ( 3 2 5 = 10,964 M~'
cm- 1 for the 4-nitropyridyl-2-dithio group linked to antibody). For the
conjugation reaction, thiol-containing drug (either DM1 or DC4) was
dissolved in DMA (N, N-dimethylacetamide) at a concentration of
approximately 10 mM. The drug (0.8 - 1.7-fold molar excess relative to the
number of linker molecules per antibody as indicated) was slowly added with
stirring to the antibody which was at a concentration of 2.5 mg/ml in buffer A
(pH 6.5 or pH 7.4) in a final concentration of 3% (v/v) DMA. The reaction was allowed to proceed at ambient temperature for the indicated times. Drug conjugated antibody was purified using a Sephadex G25 column equilibrated with buffer B (PBS, pH 6.5). For DML, the extent of drug conjugation to antibody was assessed by measuring A 2 52 and A 28 0 of the conjugate as described below. A similar approach was used for DC4 (see below).
Measurement of Releasable Pyridine-2-thione and Ab Concentration of SPP
Modified Ab.
[2281 The molar ratio of pyridine-2-thione released per mole of
antibody is calculated by measuring the A 28 0 of the sample and then the
increase in the A 343 of the sample after adding DTT (50 tL of 1 M DTT/mL of
sample). The concentration of DTT-released pyridine-2-thione is calculated
using an -343 of 8080 Mcm~1. The concentration of antibody can then be
calculated using an 6280 of 194,712 M 1 cm' after subtracting the contribution
of pyridine-2-thione absorbance at 280 nm (A 343 mpost DTT x 5100/8080)
from the total A2 80 nmmeasured before DTT addition. The molar ratio of
pyridine-2-thione:Ab can then be calculated. The mg/mL (g/L) concentration
of Ab is calculated using a molecular weight of 147,000 g/mole.
Measurement of antibody-linked 5-Nitropyridyl-2-dithio Groups and Ab
Concentration of SSNPP-Modified Ab.
[229] The molar ratio of the 4-nitropyridyl-2-dithio groups linked per
mole of antibody is calculated by measuring the A 280 and A 32 5 of the sample
without DTT treatment. The number of antibody-bound 4-nitropyridyl-2
dithio groups is calculated using an S325nnmof 10,964 M-1cm-1. The
concentration of antibody can then be calculated using an 6280 nm of 194,712
M'1cm~1 after subtracting the contribution of the 5-nitropyridyl-2-dithio group
absorbance at 280 nm (A32 snm x 3344/10964) from the total A 28 0 nm measured.
The molar ratio of 4-nitropyridyl-2-dithio groups :Ab can then be calculated.
The mg/mL (g/L) concentration of Ab is calculated using a molecular weight
of 147,000 g/mole.
Calculating Ab and DM1 component concentrations of Ab-DM1.
[230] The Ab and DM1 both absorb at the two wavelengths used to
measure each component separately, i.e., 280 and 252 nm. The components
are quantified using the following algebraic expressions which account for the
contribution of each component at each wavelength (CAb is the molar
concentration of Ab and CD is the molar concentration of DM1):
1) Total A2 80 =1 9 4 ,7 1 2 CAb + 5,700CD
2) Total A 2 52=(194,712 x 0. 3 7 )CAb+ (4.7 x 5,700) CD
Each equation is solved for CAb:
la) CAb= A280 - 5,700C 194,712
2a) CA-_A52- 26,790Cn 72,043
and an equality is set up (equation la = equation 2a) and solved for CD
CD= A252 - 0.37A 8o 24,681
[2311 Once the CD is calculated, the value is used to solve for CAb in
equation la (or 2a) above. The ratio of DM:Ab can then be calculated. The
mg/mL (g/L) concentration of antibody is calculated using a molecular weight
of 147,000 g/mole and the concentration of DM1 is calculated using a
molecular weight of 736.5 g/mole (linked DM1)
Efficiency of disulfide exchange is increased with SSNPP.
[232] As shown in Table 1, the efficiency of conjugation is enhanced
in reactions where SSNPP is used as the cross-linker compared to reactions
using SPP. The percent efficiency was calculated by dividing the value for
DM1 per antibody by the linker per antibody ratio times 100. Conjugations of
the N901 antibody using SSNPP resulted in cross-linking efficiencies of 93%
at both pH 6.5 and 7.4. The efficiency of conjugation of N901 with SPP in
these experiments was 70% at pH 6.5 and 77% at pH 7.4. The increased
efficiency with SSNPP demonstrates that a target DM1 to antibody ratio can
be achieved using antibody that is modified with a reduced number of linker
molecules. In fact, a similar drug to antibody ratio (4.3) was achieved in the
final conjugate with an antibody preparation having 4.2 (5-nitropyridyl-2 dithio)-groups per antibody introduced with SSNPP compared to an antibody having 5.6 pyridyl-2-dithio groups introduced with SPP (Table 2). The amount of drug required to obtain comparable conjugation results was therefore 25% lower for the SSNPP-modified antibody than the SPP-modified antibody under these conditions. An additional potential benefit of the increased efficiency with SSNPP is that a reduced molar excess of DM1 may be used in the conjugation reaction. A comparison of the DM1 per antibody ratios following conjugation with a range of drug equivalents in the reaction
(0.8 - 1.7 fold excess) shows that a 1.1-fold molar excess is sufficient to
achieve 100% conjugation efficiency using the SSNPP cross-linker (Figure 7).
A comparison of the time course of the reaction of DM1 with antibody that
had been modified with SSNPP or SPP is shown, for example, in Figure 8. In
each case the modified antibody was treated with a 1.1-fold molar excess of
DM1 per mole of linker incorporated. The reaction with the SSNPP-modified
antibody is considerably faster than with the SPP-modified antibody (Figure
8). Even, a molar excess of 1.7-fold is not sufficient to achieve a similar
efficiency using SPP. The ability to use 1) a lower molar excess of DM1 and
2) fewer linkers per antibody allows a reduction in the amount of drug needed
to achieve a target DM1 to antibody ratio by as much as 50% when using
SSNPP as the cross-linker instead of SPP.
[2331 The increased efficiency of conjugation using the SSNPP linker
is accomplished without compromise in the monomeric character of the conjugate and in the amount of unconjugated (free) drug associated with the antibody conjugate. SEC analysis is used to determine the amount of monomer, dimer, trimer, or higher molecular weight aggregates. Typical results of greater than 90% monomer were obtained with either linker as shown in Table 1. The level of unconjugated drug was measured by reverse phase HPLC analysis of the conjugate sample. The percent free drug for either reaction was less than 2%. In addition, shorter conjugation reaction times are possible with SSNPP compared with SPP (U.S. Patent
No.6,913,748), which may decrease loss of some antibodies that are sensitive
to prolonged exposure to organic solvent required in the conjugation reaction.
Shorter reaction times should also decrease drug loss due to DM1
dimerization, which is a competing side reaction during conjugation. The
resulting increases in yield and reduced side reactions should further
contribute to reduced DM1 requirements.
[234] The enhanced rate and efficiency of conjugation when using
SSNPP was also observed when conjugating a different drug to the antibody
demonstrating the broad applicability of this new linker reagent. A
comparison of conjugation efficiencies using SSNPP and SPP when
conjugating the N901 antibody with the DNA-alkylating drug, DC4, a
CC-1065 analogue, is shown, for example, in Table 3. By2hoursthe
reaction using the SSNPP cross-linking reagent was complete whereas the
reaction using the SPP reagent showed only 73% completeness by 2 hours and significant incorporation of drug beyond 2 hours (91% after 18 hours).
Only much prolonged reaction times may lead to 100% completeness.
Example 3. In vitro Cytotoxicity Evaluation of Maytansinoid Conjugates
of Antibodies with Thioether (Non-Cleavable) and Disulfide Linkers
Containing sulfonate group:
[235] The cytotoxic effects of the antibody-maytansinoid conjugates
with thioether and disulfide linkers containing a sulfonate groupwere typically
evaluated using a WST-8 cell-viability assay after a 4-5 day continuous
incubation of the cancer cells with the conjugates. The antigen-expressing
cancer cells (~1000-5000 cells per well) were incubated in 96-well plates in
regular growth medium containing fetal bovine serum with various
concentrations of the antibody-maytansinoid conjugates for about 5 days. The
WST-8 reagent was then added and the plate absorbance was measured at 450
nm after -2-5 h. The survival fraction was plotted versus conjugate
concentration to determine the IC50 value (50% cell killing concentration) of
the conjugate.
[236] Figures 60 and 61 show the enhancement in cytotoxicities of
Anti-CanAg (huC242) - maytansinoid conjugates with the sulfonate
containing disulfide-bonded linker (huC242-Sulfo-SPDB-DM4) bearing 6.0 to
7.6 maytansinoid/Ab compared to the conjugate with 3.3 maytansinoid/Ab
toward CanAg-positive COL0205 and COL0205-MDR cells. The potency of the conjugates with high maytansinoids loads indicate that the decoration of the antibody with up to 8 maytansinoid molecules did not affect the conjugate binding to the target COL0205 cells.
[237] Figure 64 shows the cytotoxic activities of anti-CanAg Ab
maytansinoid conjugates with similar maytansinoid load against CanAg
antigen-positive COL0205-MDR cells. The presence of sulfonate group in
disulfide linker significantly enhanced conjugate potency toward these
multiple drug resistant cells. The enhanced potency of the sulfonate-linked
conjugate is a novel finding and potentially very promising for therapeutic
applications.
[238] Figure 63 shows the cytotoxic activities of anti-EpCAM Ab
maytansinoid conjugates with similar maytansinoid load against EpCAM
antigen-positive COL0205-MDR cells. The presence of a sulfonate group in
disulfide linker significantly enhanced conjugate potency toward these
multiple drug resistant cells. The enhanced potency of the sulfonate-linked
conjugate is a novel finding and potentially very promising for therapeutic
applications.
[239] Figure 64 shows the cytotoxic activities of anti-EpCAM Ab
maytansinoid conjugates with similar maytansinoid load against EpCAM
antigen-positive HCT cells. The presence of a sulfonate group in the disulfide
linker significantly enhanced conjugate potency toward these multiple drug resistant cells. The enhanced potency of the sulfonate-linked conjugate is a novel finding and potentially very promising for therapeutic applications.
[240] Figure 65 shows the cytotoxic activities of anti-EpCAM Ab
maytansinoid conjugates with similar maytansinoid load against EpCAM
antigen-positive COL0205-MDR cells. The presence of a sulfonate group in
the thioether linker significantly enhanced conjugate potency toward these
multiple drug resistant cells. The enhanced potency of the sulfonate-linked
conjugate is a novel finding and potentially very promising for therapeutic
applications.
Example 4. Comparison of in vivo anti-tumor activity of the anti
EpCAM-maytansinoid conjugates, B38.1-SPDB-DM4 and B38.1-sulfo
SPDB-DM4, on colon cancer, COL0205 and COL0205-MDR,
xenografts:
[241] The anti-tumor effect of B38.1-SPDB-DM4 and B38.1-sulfo
SPDB-DM4 conjugates was evaluated in a xenograft model of human colon
carcinoma, COL0205 and COL0205-MDR, which was engineered to
overexpress P-glycoprotein. The cells were injected subcutaneously in the
area under the right shoulder of SCID mice. When the tumor's volume
reached approximately 200 mm3 in size, the mice were randomized by tumor
volume and divided into three groups. Each group was treated with a single
i.v. bolus of either B38.1-SPDB-DM4 (10 mg conjugate protein/kg), B38.1 sulfo-SPDB-DM4 (10 mg conjugate protein/kg) or phosphate-buffered saline
(vehicle control). Tumor growth was monitored by measuring tumor size
twice per week. Tumor size was calculated with the formula: length x width x
height x 2 .
[2421 The changes in volumes of individual COL0205-MDR tumors
are shown in Figure 66. Treatment with either conjugate resulted in
significant tumor growth delay. B38.1-sulfo-SPDB-DM4 was more
efficacious than B38.1-sulfo-SPDB-DM4 in this human colon cancer
xenograft model.
[243] The changes in volumes of individual COL0205 tumors are
shown in Figure 67. Treatment with either conjugated resulted in significant
tumor growth delay. Two of six animals treated with B38.-sulfo-SPDB-DM4
had complete tumor regressions. Thus, B38.1-sulfo-SPDB-DM4 was
significantly more efficacious than B38.1-sulfo-SPDB-DM4 in this model.
Example 5. Synthesis of procharged linkers (CX1-1):
Z-Gly-Gly-Gly-p -Ala-OtBu 0 0 0 H 0 H H O N N O Lk N 11OH H 2N O EDC , H H + 0$ H 0 H 0ol0 0'o 0
[244] 1.3 g (4.0 mmol) of Z-Gly-Gly-Gly-OH, 0.583 g (4.0 mmol) of
tert-butyl-3-aminopropionate 0.651 g (4.25 mmol) of hydroxybenzotriazole
and 0.81 g (4.23 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were weighed into a 50 mL flask then dissolved in 20 mL of dimethylformamide with magnetic stirring under a nitrogen atmosphere. After
3 hours the reaction mixture was purified in 5 mL portions by reverse phase
HPLC using a 5.0 cm x 25 cm C18 column. The column was run at 100
mL/min with deionized water containing 0.3 % formic acid 5% acetonitrile for
10 min followed by a 15 min linear gradient from 5% acetonitrile to 90%
acetonitrile. Product fractions (retention time of 19 min) were combined and
solvent was removed by rotary evaporation under vacuum to give 1.35 g
(75%) of the title compound. 'HNMR(d 6-DMSO)8.16(t,J= 5.2Hz,1H),
8.10 (t, J= 5.2 Hz, 1H), 7.82 (t, J= 5.2 Hz, 1H), 7.25 - 7.4 (in, 5H), 5.04 (s,
2H), 3.74 (d, J= 5.6 Hz, 2H), 3.67 (t, J= 6.4 Hz, 4H), 3.25 (q, J= 6.1 Hz,
2H), 2.35 (t, J= 6.8 Hz, 2H), 1.39 (s, 9H). 13 C NMR (d6 -DMSO) 170.45,
169.61, 169.00, 168.63, 156.49, 136.94, 128.30, 127.76, 127.69, 79.89, 65.51,
43.56, 42.10, 41.90, 34.89, 34.78, 27.70. HRMS ( M +Na*) Calc. 473.2012
found 473.1995.
H-Gly-Gly-Gly-p-Ala-OtBu
0 0 H H 0 H
Pd-C H2 N NN O 010% H 0 H 1O0%P0dH6-C)
[245] 1.3 g (2.89 mmol) of Z-Gly-Gly-Gly-p-Ala-OtBu was disolved
in 80 mL of 95:5 methanol:deionized water in a 250 mL parr shaker flask to which was added 0.12 g of 10% palladium on carbon. The flask was shaken under a hydrogen atmosphere (42 PSI) for 7 hours. The mixture was vacuum filtered through celite filter aid and the filtrate was concentrated by rotary evaporation under vacuum to give 0.88 g (96%) of the title compound. 'H
NMR (d-DMSO) 8.12 (t, J= 1.6Hz 2H), 8.08 (t, J=1.6 Hz, 1H), 3.75 (s,2H),
3.64 (d, J= 5.9 2H), 3.28 (bs, 2H), 3.24 (q, J= 6.0 Hz, 2H), 3.13 (s, 2H), 2.35 3 C NMR (d-DMSO) 173.38, 170.46, (t, J = 6.8 Hz, 2H), 1.39 (s, 9H).
169.18, 168.70, 79.89, 44.65, 41.95, 34.88, 34.78, 27.71. HRMS (M + H)
Calc. 317.1825, found 317.1801
Mal-Gaba-Gly-Gly-Gly-p -Ala-OtBu
0 0 0 HH H EDO / H N H+H 2N N N O EDC N N(NN N O OH 0 H 6 00 H 0 H 6
[246] 513 mg (2.8 mmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1
yl)butanoic acid, 800 mg (0.2.8 mmol) tert-butyl 3-(2-(2-(2
aminoacetamido)acetamido)acetamido)propanoate and 583 mg (3.0 mmol) N
(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were disolved
in 12 mL of dimethyl formamide and stirred for 3 hours. The reaction mixture
was purified in four equal portions by reverse phase HPLC using a 5.0 cm x
25 cm C18 column. The column was eluted at 100 mL/min with deionized water containing 0.3 % formic acid and 5% acetonitrile for 10 min followed by a 13 min linear gradient from 5% acetonitrile to 33 % acetonitrile. Product fractions (retention time of 21 min) were combined and solvent was removed by rotary evaporation under vacuum to give 832 mg (62 %) of the title compound. 'H NMR (d 6-DMSO) 8.10-8.16 (m, 2H), 8.07 (t, J= 4.8 Hz, 1H),
7.0 - 7.15(m, 1H), 3.747 (t, J= 6.0 Hz, 3H), 3.64 (d, J= 5.6 Hz, 2H), 3.41 (t,
J= 6.8, 2H), 3.1-3.33 (m, 1H), 3.19-3.26 (m, 2H), 2.348 (t, J= 6.8, 2H), 2.132 3C (t, J= 7.2 Hz, 2H), 1.67 - 1.76 (m, 2H), 1.39 (s, 9H). NMR (d6 -DMSO)
171.80, 170.98, 170.39, 169.48, 168.96, 168.56, 134.37, 79.83, 42.05, 41.83,
37.38, 34.82, 34.71, 32.26, 27.83, 23.95. HRMS (M + Na) Calc. 504.2070
found 504.2046
Mal-Gaba-Gly-Gly-Gly-p-Ala-OH
0 0
0 N 0 H H TFA HN OH 11 NN 'N !" N-rN')N, 1 N,,,O 0 H 0 H 06 0 K 0 H 0 H 06 0
[247] 820 mg (1.7 mmol) of Mal-Gaba-Gly-Gly-Gly-p-Ala-OtBu was
disolved in 9.0 mL of 95:5 trifluoroacetic acid: deionized water and
magnetically stirred for 3 hours. Solvent was removed by rotary evaporation
under vacuum to give 730 mg (100%) of the title compound. 'H NMR (d6
DMSO) 12.1 (bs, 1H), 8.05-8.20 (m, 3H), 7.82 (t, J= 6.0 Hz, 1H), 7.00 (s,
2H), 3.71 (t, J= 6.0 Hz, 4H), 3.65 (d, J= 6.0 Hz, 2H), 3.41 (t, J= 7.2 Hz, 2H),
3.26 (q, J= 5.6 Hz, 2H), 2.38 (t, J= 7.2 Hz, 2H,), 2.14 (q, J= 8.0 Hz, 2H), 3C NMR (d6 -DMSO) 172.70, 171.83, 171.01, 169.50, 1.67-1.77 (m, 2H).
168.99, 168.51, 134.38, 42.07, 41.84, 36.75, 34.70, 33.69, 32.28, 23.97
HRMS (M + Na) Calc. 448.1444 found 448.1465
Mal-Gaba-Gly-Gly-Gly-p -Ala-ONHS (CX1-1) 0 0 0 N/ H 0 H 0
OH EDC, NHS N N N - N 0 0 H a 0 H 0 H 0
[248] 76 mg (0.18 mmol) of Mal-Gaba-Gly-Gly-Gly-p-Ala-OH, 72
mg, (0.376 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride and 66 mg (0.575 mmol) of N-hydroxysuccinimide were
disolved in 1.0 mL of dimethylformamide with magnetic stirring. After 2
hours the reaction mixture was purified in two equal portions by reverse phase
HPLC using a 1.9 cm x 10 cm C8 column. The column was eluted at 18
mL/min with deionized water containing 0.3 % formic acid and 5% 1,4
dioxane for 3 min followed by a 15 min linear gradient from 5% 1,4-dioxane
to 30 % 1,4-dioxane. Product fractions (retention time 6.5 min) were collected
in a flask and immediately frozen in a dry ice acetone bath. Solvent was
removed by lyophilization at ambient temperature to give 40 mg (42%) of the
title compound. 'H NMR (d 6-DMSO) 8.08-8.11 (m, 3H), 7.99 (t, J = 6.4
Hz,1H), 7.00 (s, 2H), 3.6-3.75 (m, 6H), 3.0-3.2 (m, 4H), 2.84 ( s, 4H), 2.13 (t,
J= 7.6 Hz), 1.83-1.93 (m, 2H), 1.69-1.72 (m, 2H). HRMS (M + Na) calc.
545.1608 found 545.1638
Z-Glu(OtBu)-Gly.Gly-NH2 O HCI N 0
O O NC=NO O S OH N NH 2 OH
--H O -NH20 0 H 0 N
[249] 40 mL of Dimethyl formamide was added to 2.52 g (7.47
mmol) of Z-Glu(OtBu)-OH, 1.3 g (8.49 mmol) of hydroxybenzotriazole, 1.3 g
(7.76 mmol) of H-Gly-GlyNH2, and 1.52 g ( 7.93 mmol) of N-(3
dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. 2.5 mL (14.3
mmol) of diisopropyl ethyl amine was added and the reaction was stirred over
night. The reaction mixture was purified in three equal portions by direct
injection on a preparative 5 cm x 25 cm C18 HPLC column. The column was
run at 100 mL/min with deionized water containing 0.3 % formic acid with
5% acetonitrile for 10 min followed by a 15 min linear gradient from 5%
acetonitrile to 90% acetonitrile. Product fractions (retention time 18 - 20 min)
were combined and solvent was removed by rotary evaporation under vacuum
to give 2.9 g (83%) of the title compound. 'H NMR (400 MHz, CDC 3 ) 6 7.79
- 7.68 (in, 1H), 7.64 (s, 1H), 7.27 (q, J= 4.9, 5H), 6.90 (s, 1H), 6.42 (s, 1H),
6.35 (d, J= 6.8, 1H), 5.08 (d, J= 12.0, 1H), 4.98 (d, J= 12.2, 1H), 4.20 (dd, J
= 12.9, 7.6, 1H), 3.84-3.95 (in, 2H), 3.83 (d, J= 5.0, 2H), 2.42 - 2.19 (in, 2H),
2.07 (d, J= 6.9, 1H), 1.96 - 1.83 (in, 1H), 1.39 (s, 9H). 3 C NMR (101 MHz,
DMSO) 8 171.79, 171.65, 170.82, 168.87, 163.04, 156.08, 136.86, 128.31,
127.74, 79.64, 65.58, 53.96, 42.17, 41.81, 31.25, 27.73, 27.01.
H-Glu(OtBu)-Gly-Gly-NH 2
0 1
O0 10% Pd-C 0
NH2 H 2N OHN , NH 2 H OHN C50 a H 0 0 H 0
[250] 940 mg (2.09 mmol) of Z-Glu(OtBu)-Gly-GlyNH2 was
dissolved in 40 mL of 95:5 methanol:de-ionized water in a 250 mL glass
PARR hydrogenation shaker flak. 222 mg of 10% palladium on carbon was
added to the flask and the contents were hydrogenated with shaking under
hydrogen (40 PSI) for 4 hours. The mixture was vacuum filtered though celite
filter aid and solvent was removed from the filtrate by rotary evaporation to
give 640 mg (94%) of the title compound. 'H NMR (400 MHz, DMSO) 6
4.03 (s, 1H), 3.75 (d, J= 3.3, 2H), 3.63 (s, 2H), 3.30 - 3.22 (in, J= 3.6, 1H),
3.14 - 3.10 (in, 1H), 2.27 (t, J= 7.9, 2H), 1.84 (td, J= 13.6,7.4, 1H), 1.63 (td,
J = 15.0, 7.5, 1H), 1.39 (s, 9H). 3C NMR (101 MHz, MeOD) 8 176.53,
174.24, 172.00, 170.32, 81.82, 55.21, 43.64, 43.16, 40.44, 32.31, 30.45, 28.41.
.HRMS (M + H) Calc. 317.1825 found 317.1800.
E001008-28 Mal-Gaba-Gu(OtBu)-Gy-Gy-NH2
0 K 0 K 0O 10% Pd-C 0 0
O HN NH 2 H2N O \ HN NH2 H0 H 0 NH
[2511 603 mg (1.9 mmol) of H-Glu(OtBu)-Gly-Gly-NH2, 372 mg
(2.03 mmol) of Mal-Gaba-OH and 430 mg (2.24 mmol) of N-(3
dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were dissolved in
4.5 mL of dimethyl formamide and 800 pL of dichloromethane. The reaction
was stirred for 3 hours at ambient temperature. The reaction mixture was
purified in two equal portions by direct injection on a preparative 5 cm x 25
cm C18 HPLC column. The column was run at 100 mL/min with deionized
water containing 0.3 % formic acid 5% acetonitrile for 10 min followed by a
15 min linear gradient from 5% acetonitrile to 90% acetonitrile. Product
fractions (retention time 17.4 - 19.2 min) were combined and solvent was
removed by rotary evaporation under vacuum to give 2.9 g (83%) of the title
compound. 'H NMR (400 MHz, CDC 3) 8 8.16 (t, J= 5.7, 1H), 8.06 (d, J=
7.4, 1H), 7.99 (t, J 5.8, 1H), 7.19 (s, 1H), 7.06 (s, 2H), 4.18 (dd, J= 13.4,
7.9, 1H), 3.70 (d, J 5.7, 2H), 3.62 (d, J= 5.8, 2H), 3.42 - 3.37 (in, 2H), 2.23
(t, J= 8.0, 2H), 2.12 (dd, J= 8.1, 6.4, 2H), 1.87 (dt, J= 14.2, 7.9, 1H), 1.70
(dt, J= 13.7, 6.8, 2H), 1.38 (s, 9H). 1 3C NMR (101 MHz, DMSO) 8 173.12,
171.77, 171.65, 171.03, 170.79, 168.89, 134.43, 79.62, 52.02, 42.14, 41.81,
36.80, 32.29, 31.22, 27.73, 26.95, 24.02. HRMS (M + Na*) Cale. 504.2070
found 504.2053.
Mal-Gaba-Glu(OH)-Gly-Gly-NH 2
0 0 TFA O OH 0 0 0 0 O N N HN N NH 2 N N HN NH 2 O H O H HN H 0 H 0
[252] 105 mg (0.218 mmol) of Mal-Gaba-Glu(OtBu)-Gly-Gly-NH2
was dissolved in 5 mL of 95:5 trifluoroacetic acid:de-ionized water and
magnetically stirred for 2 hours. Solvent was removed by rotary evaporation
and residue was taken up in 6 mL acetonitrile + 1.5 mL toluene to give a
suspension. Solvent was evaporated from the suspension by rotary
evaporation under vacuum to give 92 mg (100%) of the title compound. 'H
NMR (400 MHz, DMSO) 8 6.99 (s, 2H), 4.18 (dd, J= 8.2, 5.7, 1H), 3.70 (s,
2H), 3.61 (s, 2H), 3.40 (t, J= 6.8, 2H), 2.26 (t, J= 7.8, 2H), 2.19 - 2.05 (m,
2H), 1.90 (dt, J= 13.7, 7.4, 1H), 1.73 (dt, J= 14.2, 7.5, 3H). "C NMR (101
MHz, DMSO) 6 173.76, 171.72, 170.99, 170.70, 168.81, 134.37, 52.00, 41.97,
41.63, 36.75, 32.19, 29.95, 26.79, 23.93.
Mal-Gaba-Glu(ONHS)-Gy-Gly-NH2 O 0 N-OH O OH ylHCI 0 0 0 000 N -HN H NH2 0 0 O H 0 H 0 IN N HN N NH 2 H N 0 H0 H 0
[2531 94 mg (0.22 mmol) of Mal-Gaba-Glu(OH)-Gly-Gly-NH 2, 75
mg (0.65 mmol) N-hydroxysuccinimide and 110 mg (0.57 mmol) of N-(3
dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were magnetically
stirred in 1 mL of dimethyl formamide for 3 hours. The crude reaction
mixture was purified in three equal portions by direct injection on a 1.9 cm x
10 cm C8 column. The column was run at 18 m/min with deionized water
containing 0.3% formic acid and 5% 1,4-dioxane for 3 min followed by an 18
min linear gradient from 5% 1,4-dioxane to 30% 1,4-dioxane. Product
fractions (retention time 7.3 min) were collected in a flask and immediately
frozen in a dry ice/acetone bath. The combined frozen material was
lyophilized to give 80 mg (70 %) of the title compound. 'H NMR (400 MHz,
DMSO) 6 8.20 (t, J= 5.4, 1H), 8.13 (d, J= 7.3, 1H), 8.03 (t, J= 5.6, 1H), 7.21
(s, 1H), 7.06 (s, 1H), 7.01 (s, 2H), 4.29 (dd, J= 13.7, 6.5, 1H), 3.84 - 3.69 (m,
2H), 3.63 (d, J= 5.7, 2H), 3.57 (s, 2H), 3.41 (t, J= 6.8, 2H), 2.81 (s, 3H), 2.78
- 2.69 (m, 2H), 2.15 (dd, J= 9.1, 6.2, 1H), 2.10 - 1.95 (m, 1H), 1.88 (dt, J=
17.0, 7.5, 1H), 1.73 (dd, J= 14.0, 6.9, 2H). HRMS (M + Na) Calc. 545.1608
found 545.1627.
Example 6. Synthesis of positively charged linker
H 3C, O HCl*H 2N 37% HCHO ,N 1). NaOH
NaB(CN)H 3 H 3C 2). PySSPy, pH 7 213 217
H3 C, ,CH 3 H3C,NCH3 O N NHS/DCC 3 N ./H - SS COOH DMA S O-N N 218 -N 219 0 0
3-(Dimethylamino)dihydrothiophen-2(3H)-one(217).
[254] 3-aminodihydrothiophen-2(3H)-one hydrochloride (213) (1.0 g,
6.51 mmol) and formaldehyde (3 ml, 40.3 mmol) in methanol was added
sodium cynoboronhydride (0.409 g, 6.51 mmol) in five portions in 1 h. After
being stirred for 2 h, the mixture was evaporated, redissolved in EtAc, washed
with 1 M NaH 2PO 4 , dried over MgSO 4 , filtered, concentrated and purified by
SiO2 column eluted with MeOH/DCM (1:30) to afford 0.812 g (86%) of the
title compound. 1H NMR (CDC1 3) 3.49 (dd, 1H, J = 6.3, 12.1 Hz), 3.24 (m,
2H), 2.42 (s, 6H), 2.38 (m, 1H), 2.21 (m, 1H); 13C NMR 206.58, 73.24,
41.62,27.47,25.51; ESI MS m/z+146.0 (M +H), 168.0 (M +Na).
2-(dimethylamino)-4-(pyridin-2-yldisulfanyl)butanoic acid (218).
[2551 3-(dimethylamino)dihydrothiophen-2(3H)-one (217) (0.95 g,
6.54 mmol) was stirred in 15 ml of 0.5 M NaOH and 10 ml of methanol
solution for 30 min, nutralized with H3 PO4 to pH 7.2, and 1,2-di(pyridin-2
yl)disulfane (5.76 g, 26.2 mmol) in 50 ml of methanol was added. The
mixture was stirred overnight, concentrated, washed with EtAc and the
aquoues solution was loaded on C-18 column, eluted from 5% methanol in
0.01% formic acid to 30% methanol in 0.01% formic acid to afford the title
product (368 mg, 20.65 % yield). 1 H NMR (CD130D) 8.31 (dd, 1H, J = 0.7,
4.7 Hz), 7.77 (m, 2H), 7.15 (dd, 1H, J = 0.8, 5.8 Hz), 3.22 (m, 1H), 2.85 (m,
2H), 2.51 (s, 6H), 2.05 (m, 2H); 13C NMR 175.00, 161.28, 150.46, 139.40,
122.60, 121.49, 71.20, 42.46, 36.29, 29.88; ESI MS m/z+ 272.9 (M + H),
295.0 (M+Na).
2,5-dioxopyrrolidin-1-yl 2-(dimethylamino)-4-(pyridin-2
yldisulfanyl)butanoate (219)
[256] 2-(dimethylamino)-4-(pyridin-2-yldisulfanyl)butanoic acid
(218) (92 mg, 0.338 mmol), 1-hydroxypyrrolidine-2,5-dione (65 mg, 0.565
mmol) and EDC (185 mg, 0.965 mmol) was stirred in 3 ml of DMA at 50°C
overnight. The mixture was evaporated and purified on a SiO 2 column eluted
with from1:10 to 1:4 of methanol/CH 2Cl2 to afford 43 mg (35%) of the title
product. 1 H NMR (CD130D) 8.40 (m, 1H), 7.83 (m, 2H), 7.22 (m, 1H), 3.34
(in, 111), 2.82 (in, 2H), 2.75 (s, 4H), 2.66 (s, 6H), 1.98 (in, 2H); "C NMR
177.21, 161.78, 161.12, 150.68, 139.37, 122.70, 121.66, 70.80, 44.16, 43.15,
36.06, 27.38; ESI MS m/z+ 369.2 (M + H).
Example 7. Preparation of huMy9-6-CX1-1-DM1 procharged linker
coniugates:
[2571 The following stock solutions were used: 39.6 mM DM1 in
DMA; (2) 17.8 mM solution of CX1-1 linker in DMA; (3) 200 mM succinate
buffer pH 5.0 with 2 mM EDTA. The reaction mixture containing between 8,
12 or 16 equivalents of linker to antibody were added to a solution of the
antibody at 4 mg/ml in 90% phosphate buffer pH 6.5)/ 10% DMA and allowed
to react for 2h at 25°C. pH 5.0, followed by reaction with DM1.
[258] The Ab conjugate was separated from excess small molecule
reactants using a G25 column equilibrated in PBS pH 7.4. The purified
conjugate was allowed to hold for 2d at 25'C to allow any labile drug linkages
to hydrolyze and then the conjugate was further purified from free drug by
dialysis in PBS overnight, and then 10 mM histidine/130 mM glycine buffer
pH 5.5 (x o/n). The dialyzed conjugate was filtered using a 0.2 um filter and
assayed by UV/Vis to calculate number of maytansinoids per Ab using known
extinction coefficients for maytansinoid and antibody at 252 and 280 nm. The
recovery was -70% and number of maytansinoids/antibody measured for each
conjugate ranged from 3.7 to 6.8 depending on the linker excess used.
Example 8. In vivo Pharmacokinetics:
[2591 The plasma pharmacokinetics of charged Sulfo-Mal linker
conjugates of a humanized antibody C242 with 3H-labeled-DM4 (3.5 and 6.4
DM4/Ab) in CD-1 mice were analyzed by antibody ELISA and by 3H
counting (Figure 72). The Ab-Sulfo-Mal-[ 3H]-DM4 conjugates bearing 3.5
and 6.4 D/A were dosed i.v. at 12.9 and 7.9 mg/kg (antibody dose)
respectively. The antibody values of plasma samples were measured by
ELISA (based on capture using goat-anti-hulgG antibody and detection using
donkey-anti-huIgG antibody-horseradish peroxidase conjugate) and by 3H
counting (scintillation counting). Figure 72 A shows that these two
3H-counting measurements of conjugate concentrations by ELISA and by
showed similar values for each conjugate. Both the 3.5 and 6.4 D/A
Antibody-Sulfo-Mal-DM4 conjugates showed good plasma stability over 4
weeks with half-life of approximately 14.9 days and 9.7 days respectively,
which are similar to the half-life of approximately 11.8 days for the
unconjugated antibody. The DM4/Ab ratio of the two Ab-Sulfo-Mal-DM4
conjugates (initially 3.5 and 6.4 D/A) were also stable over 4 weeks in plasma
circulation, importantly even at the relatively high 6.4 D/A load (Figure 72 B).
The half life of Sulfo-Mal-linked huC242 Ab-Sulfo-Mal-DM4 conjugate with
3.5 D/A load dosed at 12.9 mg/kg was 14.9 days (AUC = 38449 hr. tg/mL),
compared to a half life of 12.6 days (AUC = 25910 hr.pg/mL) for SMCC
linked huC242 Ab-SMCC-DM1 conjugate with a similar 4.2 D/A load dosed at 12 mg/kg, and thus was much improved over that of the SMCC conjugate
(Figure 38 B).
Table 1. Comparison of SSNPP and SPP linker in the conjugation of N901 antibody with DM1. Conjugation was conducted for 2 hours at the indicated pH using a 1.7-fold molar excess of DM1 per linker. % SEC Analysis
Linker pH Linker/Ab DM1/Ab % free Efficiency drug Monomer Dimer Trimer HMW
SSNPP 7.4 4.1 3.8 93 0.8 91.9 6.3 0.6 0.1
SPP 7.4 5.6 4.3 77 1.8 93.6 4.9 0.4 0.2
SSNPP 6.5 4.0 3.7 93 0.9 - - -
SPP 6.5 6.6 4.6 70 1.9 - -
Table 2. Reduced linker to antibody ratio required to reach target DM1 to antibody ratio with SSNPP as linker. Conjugation was conducted for 2 hours at pH 7.4 using a 1.1-fold molar excess of DM1 per linker.
Linker Linker/Ab DM1/Ab SSNPP 4.2 4.3 SPP 5.6 4.3
Table 3. Comparison of SSNPP and SPP linker in the conjugation of N901 antibody with DC4. Conjugation was conducted for the indicated time at pH 7.4 using a 1.4-fold molar excess of DC4 per linker.
Linker Time, h Linker/Ab DC4/Ab efficiency SSNPP 2 4.2 4.3 102 SSNPP 18 4.2 4.1 98 SPP 2 5.6 4.1 73 SPP 18 5.6 5.1 91
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
127a
Claims (25)
- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a cell-binding agent-drug conjugate of formula (II)R7 R8 R3 R4 Y z D C 1nR9 RiR 5 R6m 1 2 _q (II) wherein: the cancer is selected from a group consisting of breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gastric cancer, squamous cancer, small-cell lung cancer, and testicular cancer; CB represents a cell-binding agent; D represents a drug linked to the cell-binding agent by a disulfide, thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amide bond; R 1, R2 , R3 , R4 , R 5, R 6, R7 , R8 , R9 , and Rio are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a charged substituent selected from anions selected from S03-. X-SO3-, OP03 2 -, X-OP032-, P032-, X-P032-, and cations selected from a nitrogen containing heterocycle, N'RiiR 12 R 13 and X-N'RiR 12 R 13 , or a phenyl; wherein: R 1 , R 12 and R13 are the same or different and are linear alkyl having from I to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms and X represents phenyl or a linear alkyl from 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms; 1, m and n are 0 or an integer from 1 to 4; A is a phenyl or substituted phenyl, wherein the substituent is a linear alkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl having from 3 to 6 carbon atoms, or a charged substituent selected from anions selected from SO3, X-S03-, OP0 3 2 , X-OP0 32 , P0 32 , X-P0 3 2C02-, and cations selected from a nitrogen containing heterocycle, N'RR 12R1 3 and X N'RiiRI 2R 3 , wherein X has the same definition as above, and wherein g is 0 or 1; Z is an optional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, wherein p is 0 or an integer from 2 to about 1000, or Fl-E l-P-E2-F2 unit in which E l and E2 are the same or different and are C=O,0, or NR14, wherein R 14 is H, a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20 amino acids in length, wherein El or E2 can be linked to the peptide through the terminal nitrogen, terminal carbon or through a side chain of one of the amino acids of the peptide; and Fl and F2 are the same or different and are an optional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, wherein p is 0 or an integer from 2 to about 1000, provided that when Z is not F1-El-P-E2-F2, at least one of R1 , R2 , R3 , R4 , R5 , R6 , R7, R8, R9, and Rio when present is a charged substituent or when g is 1, at least one of A, R 1 , R 2, R 3, R 4, R 5 , R6 , R 7, R 8, R 9, and Rio when present is acharged substituent; and Y represents a carbonyl, thioether, amide, disulfide, or hydrazone group; and q represents an integer from 1 to 20.
- 2. The method of claim 1, wherein D is selected from maytansinoids, CC-1065 analogs, morpholino doxorubicin, taxanes, calicheamicins, auristatins, pyrrolobenzodiazepine dimmer, siRNA or a combination thereof, and pharmaceutically acceptable salts, acids or derivatives of any of the above.
- 3. The method of claim 1, wherein the cell-binding agent binds to target cells selected from tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes, cells expressing one or more of IGF-IR, CanAg, EGFR, EphA2 receptor, MUC1, MUC16, VEGF, TF, EpCAM, CD2, CD3, CD4, CD5, CD6, CD11, CD11a, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, EphA receptors, EphB receptors, EGFr, EGFRvIII, HER2/neu, HER3, mesothelin, cripto, alphavbeta integrin, alphavbeta5 integrin, alphavbeta6 integrin, Apo2, and C242 antigens; and cells expressing insulin growth factor receptor, epidermal growth factor receptor, or folate receptor.
- 4. The method of claim 1, wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that binds a target cell, a chimeric antibody, a chimeric antibody fragment that binds to a target cell, a domain antibody, a domain antibody fragment that binds to a target cell, adnectins that mimic antibodies, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient transport molecule.
- 5. The method of claim 4, wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment thereof.
- 6. The method of claim 4, wherein the antibody is a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof.
- 7. The method of claim 4, wherein the antibody is a human antibody, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment thereof.
- 8. The method of claim 4, wherein the antibody is a chimeric antibody, a chimeric antibody fragment, a domain antibody, or a domain antibody fragment thereof.
- 9. The method of claim 7, wherein the antibody is My9-6, B4, C242, N901, DS6, CNTO 95, B-B4, trastuzumab, pertuzumab, bivatuzumab, sibrotuzumab, pertuzumab, rituximab, or an antibody that binds to EpCAM, EphA2 receptor, CD38, IGF-IR, or folate receptor.
- 10. The method of claim 3, wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, and testicular cancer cells.
- 11. The method of any one of claims 1-10, wherein one of R1 , R 2, R3 , R4, R9 and Rio is a charged substituent selected from S03-, X-S3-, OP0 3 2 -, X-OP0 32-, N*RiiR1 2R1 3 and X N*RiR12R13, and the rest are H; 1, g and m are each 0; n is 1; and D is a maytansinoid.
- 12. The method of claim 11, wherein one of R1 , R2 , R3 , R4 , R9 and Rio is S03- or X S03-, the rest are H; 1, g and m are each 0; and n is 1.
- 13. The method of any one of claims 1-12, wherein Z is an F-El-P-E2-F2 unit, wherein E l and E2 are the same or different and are C=O or NR 14 , wherein R 14 is H, a linear alkyl having 1-6 carbon atoms or a branched or cyclic alkyl having from 3 to 6 carbon atoms; and P is a peptide unit between 2 and 8 amino acids.
- 14. The method of claim 13, wherein R 14 is H or a linear alkyl having 1-6 carbon atoms; and P is a peptide unit between 2 and 5 amino acids; and Fl and F2 are the same or different and are optional polyethyleneoxy units of formula (OCH 2 CH2 )p, where p is 0 or an integer from 2 to 24.
- 15. The method of claim 14, wherein p is 0.
- 16. The method of claim 15, wherein P is gly-gly-gly.
- 17. The method of any one of claims 1-10, wherein the conjugate is represented by any one of the following:0 CB SH SO 3H -q0CB, N N H D' SO 3H o0 0 SO 3HCB N NNJI N H D' 0 q,00 0UH H~CB NNNNNwherein D'-S- or o is the drug linked to the cell-binding agent by adisulfide or a thioether bond.
- 18. The method of claim 17, wherein the conjugate is represented by the following:H SO3H -D]
- 19. The method of claim 18, whereinD isa maytansinoid.
- 20. The method of claim 19, wherein D is DM1 or DM4.
- 21. The method of claim 20, wherein D is DM4.
- 22. The method of any one of claims 1-21, wherein the cell-binding agent is an antibody that binds to a folate receptor.
- 23. The method of claim 22, wherein the folate receptor is folate receptor 1 (FOLR1).
- 24. The method of claim 22 or 23, wherein the method is for treating a cancer that expresses a folate receptor.
- 25. The method of any one of claims 1-24, wherein the cancer is ovarian cancer.WHAT IS CLAIMED IS:1. A cell-binding agent-drug conjugate of formula (II)R7 R 8 R3 R4 Y Z D CB'n Agn R9 RIO R 5R6 1 2_ q(II)wherein:CB represents a cell-binding agent;D represents the drug linked to the cell-binding agent by a disulfide,thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amidebond;R1, R2 , R3 , R4 , R5, R 6, R7 , R 8, R9 , and R 10 are the same or different andare H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkylhaving from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms, a charged substituent selected from anionsselected from So 3 -.X-SO3, OPO 32 -, X-OPO 3 2 , P03, X-P 2 3 , C0 -,2 andcations selected from a nitrogen containing heterocycle, NR1 1 R 12R1 3 and XN+RIR12R13, or a phenyl; wherein:Rn, R1 2and R 13 are same or different and are H, linear alkyl havingfrom 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbonatoms and X represents phenyl or a linear alkyl from 1 to 6 carbon atoms, orbranched or cyclic alkyl having from 3 to 6 carbon atoms;1, m and n are 0 or an integer from 1 to 4;A is a phenyl or substituted phenyl, wherein the substituent is a linearalkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, or a charged substituent selected from anionsselected from S03 ~, X-S0 3 , OP0 32 -, X-OP 2 3 -, PO 32, X-P0 3 2 , C0 2-, andcations selected from a nitrogen containing heterocycle, N*RR 12 R13 and XN*RuR 12R 3 , wherein X has the same definition as above, and wherein g is 0or 1;Z is an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p, whereinp is 0 or an integer from 2 to about 1000, or F1-E-P-E2-F2 unit in which Eland E2 are the same or different and are C=O,0, or NR14, wherein R 14 is H,a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20 aminoacids in length, wherein El or E2 can be linked to the peptide through theterminal nitrogen, terminal carbon or through a side chain of one of the aminoacids of the peptide; and Fl and F2 are the same or different and are anoptional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, wherein p is 0 or an integer from 2 to about 1000, provided that when Z is not F1-El-P-E2-F2, at least one of R1 , R2, R3, R4 , R5 , R6 , R7, R8 , R9 , and RIO is a charged substituent1 , R 2, R 3, R 4 , R 5 , R6 , R7, R8 , R 9, and Rio is a or when g is 1, at least one of A, Rcharged substituent;Y represents a carbonyl, thioether, amide, disulfide, or hydrazonegroup; and q represents an integer from 1 to 20.2. The conjugate of claim 1, wherein D is selected from thiotepa;cyclophosphamide (CYTOXANC TM)); alkyl sulfonates selected from busulfan,improsulfan and piposulfan; aziridines selected from benzodopa, carboquone,meturedopa, and uredopa; ethylenimines; and methylamelamines; acetogeninsselected from bullatacin and bullatacinone; a camptothecin; bryostatin;callystatin; CC-1065; adozelesin, carzelesin or bizelesin synthetic analoguesof CC-1065; cryptophycins; dolastatin; duocarmycin; KW-2189 or CBI-TMIsynthetic analogues of duocarmycin,; eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards selected from chlorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g.calicheamicin, especially calicheamicin gammal and calicheamicin theta I; dynemicin, including dynemicin A; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L norleucine, doxorubicin epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites selected from methotrexate and 5-fluorouracil (5-FU); folic acid analogues selected from denopterin, methotrexate, pteropterin, trimetrexate; purine analogs selected from fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimnidine analogs selected from ancitabine, azacitidine,6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, 5-FU; androgens selected from calusterone, dromostanolonepropionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher selected fromfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; maytansinoids selected frommaytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK*; razoxane; rhizoxin; sizofiran;spirogermanium; tenuazonic acid; triaziquone; 2, 2',2"-trichlorotriethylamine;trichothecenes selected from T-2 toxin, verracurin A, roridin A andanguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol;mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");cyclophosphamide; thiotepa; taxanes; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs selected fromcisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO);retinoic acid; capecitabine; anti-hormonal agents selected from anti-estrogensincluding tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andtoremifene (Fareston); and anti-androgens selected from flutamide,nilutamide, bicalutamide, leuprolide, and goserelin, siRNA or a combinationthereof; and pharmaceutically acceptable salts, acids or derivatives of any ofthe above.3. The conjugate of claim lor 2, wherein D is selected frommaytansinoids, CC-1065 analogs, morpholino doxorubicin, taxanes,calicheamicins, auristatins, pyrrolobenzodiazepine dimmer, siRNA or a combination thereof, and pharmaceutically acceptable salts, acids or derivatives of any of the above.4. The conjugate of claim 1, wherein the cell-binding agent bindsto target cells selected from tumor cells, virus infected cells, microorganisminfected cells, parasite infected cells, autoimmune cells, activated cells,myeloid cells, activated T-cells, B cells, or melanocytes, cells expressing oneor more of IGF-IR, CanAg, EGFR, EphA2 receptor, MUC1, MUC16, VEGF,TF, MY9, anti-B4, EpCAM, CD2, CD3, CD4, CD5, CD6, CD11, CD 11a,CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44,CD56, CD79, CD105, CD138, EphA receptors, EphB receptors, EGFr,EGFRvIII, HER2/neu, HER3, mesothelin, cripto, alphavbeta 3, integrin,alphavbeta 5integrin, alphavbeta integrin, Apo2, and C242 antigens; and cellsexpressing insulin growth factor receptor, epidermal growth factor receptor, orfolate receptor.5. The conjugate of claim 1, wherein the cell-binding agent is anantibody, a single chain antibody, an antibody fragment that binds to the targetcell, a monoclonal antibody, a single chain monoclonal antibody, or amonoclonal antibody fragment that binds the target cell, a chimeric antibody, achimeric antibody fragment that binds to the target cell, a domain antibody, adomain antibody fragment that binds to the target cell, adnectins that mimicantibodies, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, acolony stimulating factor, or a nutrient-transport molecule.6. The conjugate of claim 5, wherein the antibody is a resurfacedantibody, a resurfaced single chain antibody, or a resurfaced antibodyfragment thereof.7. The conjugate of claim 5, wherein the antibody is a monoclonalantibody, a single chain monoclonal antibody, or a monoclonal antibodyfragment thereof.8. The conjugate of claim 5, wherein the antibody is a humanantibody, a humanized antibody or a resurfaced antibody, a humanized singlechain antibody, or a humanized antibody fragment thereof.9. The conjugate of claim 5, wherein the antibody is a chimericantibody, a chimeric antibody fragment, a domain antibody, or a domainantibody fragment thereof.10. The conjugate of claim 8, wherein the antibody is My9-6, B4,C242, N901, DS6, EpCAM, EphA2 receptor, CD38, IGF-IR, CNTO 95, BB4, trastuzumab, pertuzumab, bivatuzumab, sibrotuzumab, pertuzumab, orrituximab.11. The conjugate of claim 4, wherein the tumor cells are selectedfrom breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectalcancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancercells, and testicular cancer cells.12. A method of treating a tumor comprising administering to asubject in need of treatment a therapeutically effective amount of a conjugateof claim 1.13. A cross linker represented by formula (I)R7 R 8 R3 R4 Y- Z" QR 9 RIO R 5 R 6 R1 R2(I)wherein:Y' represents a functional group that enables reaction with a cellbinding agent;Q represents a functional group that enables linkage of a cytotoxic drug via a disulfide, thioether, thioester, peptide, hydrazone, ester, ether,carbamate or amide bond;R1, R2, R3 , R4 , R5, R6, R7, R8, R9 , and RIO are the same or different andare H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkylhaving from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms, a charged substituent selected fromanionsselected from SO3, X-S0 3 ~, OP0 32 , X-OP0 3 2 , P0 3 2 , X-P0 3 2 , C0 2-,and cations selected from a nitrogen containing heterocycle, N*RnR 12R 3,andX-NR 1 1R 12 R 3 , or a phenyl, wherein:Ru, R 12 and R 13 are same or different and are H, linear alkyl havingfrom 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms;1, m and n are 0 or an integer from 1 to 4;A is a phenyl or substituted phenyl, wherein the substituent is a linearalkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, or a charged substituent selected from anions 2 2 selected from SO3, X-S0 3 ~, OP0 32 , X-OP0 3 , P0 3 -, X-P0 3 , C0 2-, andcations selected from a nitrogen containing heterocycle, N*RuR1 2R 3, andXN+R 1 R 12 R 3 , wherein X has the same definition as above, and wherein g is 0or 1; andZ is an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p, whereinp is 0 or an integer from 2 to about 1000, or F1-E1-P-E2-F2 unit in which Eland E2 are the same or different and are C=O,0, or NR14, wherein R 14 is H,a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20 aminoacids in length, wherein El or E2 can be linked to the peptide through theterminal nitrogen, terminal carbon or through a side chain of one of the aminoacids of the peptide; and F1 and F2 are the same or different and are anoptional polyethyleneoxy unit of formula (OCH2 CH2 )p, wherein p is 0 or an integer from 2 to about 1000, provided that when Z is not F1-El-P-E2-F2, at least one of R1, R2 , R3 , R4, R 5, R 6 , R7 , R8 , R9 , and RIO is a charged substituent or when g is 1, at least one of A, R1, R2 , R3 , R4, R5, R 6 , R7 , R8 , R9 , and RIO is a charged substituent.14. A compound of formula (III):R7 R8 R3 RIz& C 1nR9 RIO R5 R6 R R2 q(III)wherein:CB represents a cell-binding agent;Q represents a functional group that enables linkage of a cytotoxicdrug via a disulfide, thioether, thioester, peptide, hydrazone, ester, ether,carbamate or amide bond;R1, R2, R3 , R4 , R 5, R6, R7, R8, R9 , and RIO are the same or different andare H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkylhaving from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms, a charged substituent selected from anions2 selected from S03 ~, X-S0 3~, OP0 32 , X-OP 3 2 , P0 3 2 , X-P0 3 , C0 2-, andcations selected from a nitrogen containing heterocycle, N*RiiR1 2 R 13 and XN+RiiR 12R13, or a phenyl, wherein:R,, R 12 and R 13 are same or different and are H, linear alkyl havingfrom 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms;1, m and n are 0 or an integer from 1 to 4;A is a phenyl or substituted phenyl, wherein the substituent is a linearalkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, or a charged substituent selected from anionsselected from SO3, X-S0 3 , OP0 2 3 , X-OPO 2 3 -, P0 2 3 , X-P0 32 , C0 2-, andcations selected from a nitrogen containing heterocycle, N*RuR 12 R1 3 and XN*RIIR1 2R13, wherein X has the same definition as above, and wherein g is 0or 1;Z is an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p, whereinp is 0 or an integer from 2 to about 1000, or F1-E1-P-E2-F2 unit in which Eland E2 are the same or different and are C=O,0, or NR14, wherein R 14 is H,a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20 aminoacids in length, wherein El or E2 can be linked to the peptide through theterminal nitrogen, terminal carbon or through a side chain of one of the aminoacids of the peptide; and Fl and F2 are the same or different and are anoptional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, wherein p is 0 or an integer from 2 to about 1000, provided that when Z is not F1-E1-P-E2-F2, at least one of R1 , R2 , R3 , R4 , R5 , R6 , R7, R8 , R9, and RIO is a charged substituent1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7, R8 , R9 , and RIO is a or when g is 1, at least one of A, Rcharged substituent; andY represents a carbonyl, thioether, amide, disulfide, or hydrazonegroup; and q represents an integer from 1 to 20.15. A compound of formula (IV):R7 R 8 R R4 Y1 D Ag n m R9 R1 0 RR 6 R 1 R2 (IV)wherein:Y' represents a functional group that enables reaction with a cellbinding agent;D represents the drug linked to the cell-binding agent by a disulfide,thioether, thioester, peptide, hydrazone, ester, ether, carbamate, or amidebond;R 1, R2 , R3 , R4 , R 5, R6, R7 , R 8, R9 , and RIO are the same or different andare H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkylhaving from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms, a charged substituent selected from anions selected from So 3 -, X-S3-, OP03 2 , X-OPO 32 -, 3 -, X-PO 3 , C0 2-, and cations selected from a nitrogen containing heterocycle, N+RlR1 2R1 3 and XN+R 1 R 12R 3, or a phenyl, wherein:Ru, R1 2and R 13 are same or different and are H, linear alkyl havingfrom 1 to 6 carbon atoms, or branched or cyclic alkyl having from 3 to 6carbon atoms and X represents phenyl or a linear alkyl having from 1 to 6carbon atoms, or branched or cyclic alkyl having from 3 to 6 carbon atoms;1, m and n are 0 or an integer from 1 to 4;A is a phenyl or substituted phenyl, wherein the substituent is a linearalkyl having from 1 to 6 carbon atoms, or a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, or a charged substituent selected from SO3, X-S03-, 2-2- OP0 3 2 , X-OP0 3 -, P0 3 2--, X-P0 32-, C0 2 -, a nitrogen containing heterocycle,N*R, R12 R 31or X-N*R R1 2 R13, wherein X has the same definition as above,and wherein g is 0 or 1; andZ is an optional polyethyleneoxy unit of formula (OCH 2 CH 2 )p, whereinp is 0 or an integer from 2 to about 1000, or F1-E1-P-E2-F2 unit in which Eland E2 are the same or different and are C=,0, or NR14, wherein R14 is H,a linear alkyl having from 1-6 carbon atoms, a branched or cyclic alkyl havingfrom 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynylhaving from 2 to 6 carbon atoms; P is a peptide unit between 2 and 20 aminoacids in length, wherein El or E2 can be linked to the peptide through theterminal nitrogen, terminal carbon or through a side chain of one of the amino acids of the peptide; and F1 and F2 are the same or different and are an optional polyethyleneoxy unit of formula (OCH 2 CH2 )p, wherein p is 0 or an integer from 2 to about 1000, provided that when Z is not F1-E1-P-E2-F2, at least one of R1 , R2, R3, R 4 , R5 , R6 , R7 , R8 , R9 , and RIO is a charged substituent or when g is 1, at least one of A, R 1, R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , and Rio is a charged substituent.16. A pharmaceutical composition comprising an effective amountof the conjugate of claim 1, a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier, diluent or excipient.
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US5219564A (en) * | 1990-07-06 | 1993-06-15 | Enzon, Inc. | Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon |
US5137877B1 (en) * | 1990-05-14 | 1996-01-30 | Bristol Myers Squibb Co | Bifunctional linking compounds conjugates and methods for their production |
CA2481996A1 (en) * | 2002-04-08 | 2003-10-23 | Amura Therapeutics Limited | Charge-balanced chemoselective linkers |
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