Targeted alpha particle therapy using actinium-255 conjugates
First Claim
1. An 225Ac complex comprising a functionalized chelant compound having the structure wherein R is independently —
- CHQCO2X;
Q is independently hydrogen;
—
C1-4-alkyl or —
(C1-2-alkyl) phenyl;
X is independently hydrogen;
benzyl or —
C1-4-alkyl; and
Z1 is —
(CH2)nY wherein n is 1 to 10 and Y is an electrophilic or nucleophilic moiety and Z2 is R;
or, in the alternative, Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids;
with the proviso that when R and Z2 are CH2CO2H, Z1 is not (CH2)(1-6)Y;
wherein Y comprises a para-substituted phenyl group, said phenyl substituent having a free end group Comprising —
NO2, —
NH2, —
NCS, —
COOH, —
OCH2COOH, —
OCH2COOH, —
NHCOCH2Br or —
NHCOCH2I;
or a pharmaceutically acceptable salt thereof complexed with 225Ac;
further comprising an antibody or fragment thereof, a growth factor or a cytokine that is covalently attached to Y or to said peptide linker.
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Accused Products
Abstract
The present invention provides functionalized chelants and a method of treating cancerous cells with alpha particles comprising the step of administering a pharmacologically effective dose of an 225Ac conjugate comprising a functionalized chelant
R is independently CHQCO2X; Q is independently hydrogen; C1-C4 alkyl or (C1-C2 alkyl) phenyl; X is independently hydrogen; benzyl or C1-C4 alkyl; Z1 is (CH2)nY where n is 1-10 and Y is an electrophilic or nucleophilic moiety and Z2 is R; or, alternatively, Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids; said Y or said peptide linker covalently attached to an antibody or fragment thereof, or other biologic molecule; or a pharmaceutically acceptable salt thereof, complexed with 225Ac. These biologic molecule binds to cancerous cells and 225Ac or its daughters emit alpha particles into said cancerous cells effecting treatment.
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Citations
20 Claims
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1. An 225Ac complex comprising a functionalized chelant compound having the structure
wherein R is independently — - CHQCO2X;
Q is independently hydrogen;
—
C1-4-alkyl or —
(C1-2-alkyl) phenyl;
X is independently hydrogen;
benzyl or —
C1-4-alkyl; and
Z1 is —
(CH2)nY wherein n is 1 to 10 and Y is an electrophilic or nucleophilic moiety and Z2 is R;
or, in the alternative,Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids;
with the proviso that when R and Z2 are CH2CO2H, Z1 is not (CH2)(1-6)Y;
wherein Y comprises a para-substituted phenyl group, said phenyl substituent having a free end group Comprising —
NO2, —
NH2, —
NCS, —
COOH, —
OCH2COOH, —
OCH2COOH, —
NHCOCH2Br or —
NHCOCH2I;
or a pharmaceutically acceptable salt thereof complexed with 225Ac;
further comprising an antibody or fragment thereof, a growth factor or a cytokine that is covalently attached to Y or to said peptide linker. - View Dependent Claims (2)
- CHQCO2X;
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3. A method of treating cancerous cells with alpha particles in an individual in need of such treatment comprising the step of:
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administering a Pharmacologically effective dose of an 225Ac conjugate comprising a functionalized chelant having the structure wherein R is independently CHQCO2X;
Q is independently hydrogen;
C1-4-alkyl or (C1-2-alkyl) phenyl;
X is independently hydrogen;
benzyl or C1-4-alky;
Z1 is (CH2)nY wherein n is 1 to 10 and Y is an electrophilic or nucleophilic moiety and Z2 is R;
or, in the alternative,Z1 is hydrogen and Z2 is a peptide linker composed of 1-10 amino acids; and
an antibody or fragment thereof, a growth factor or a cytokine specifically targetable to said cancerous cells covalently attached to said Y or to said peptide linker;
or a pharmaceutically acceptable salt thereof, complexed with 225Ac; and
targeting said antibody or antibody fragment, growth factor or a cytokine to said cancerous cells wherein said 225Ac or alpha particle-emitting daughters thereof emit said alpha particles Into said cancerous cells, said alpha particles causing a cytotoxic effect on said cancerous cells, thereby effecting treatment of said individual. - View Dependent Claims (4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
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14. A method of treating cancerous cells with alpha particles in an individual in need of such treatment comprising:
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administering a pharmacologically effective dose of an 225Ac conjugate comprising a functionalized chelant having the structure wherein R and Z2 are CH2CO2H; and
Z1 is (CH2)nY wherein n is 1 to 10 and Y is an electrophilic or nucleophilic moiety;
said Y covalently attached to a monoclonal antibody;
or a pharmaceutically acceptable salt thereof;
complexed with 225Ac;
binding said monoclonal antibody to said cancerous cells;
internalizing said 225Ac within said cancerous cells, and emitting said alpha particles from said 225Ac or its daughters, said alpha particles remaining within said cancerous cells, wherein said alpha particles cause a cytoxic effect on said cancerous cells thereby effecting treatment of said individual. - View Dependent Claims (15, 16, 17, 18, 19, 20)
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Specification