Camptothecin-binding moiety conjugates
AssigneeImmunomedics, Inc.
InventorsSerengulam V. Govindan, David M. Goldenberg, Sung-Ju Moon
Life of this patent
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Abstract
The invention relates to therapeutic conjugates with improved ability to target various diseased cells containing a targeting moiety (such as an antibody or antibody fragment), a linker and a camptothecin as a therapeutic moiety, and further relates to processes for making and using the said conjugates.
Claims34
A method for treating a cancer, comprising administering a pharmaceutical composition to a subject with cancer, wherein the composition comprises a conjugate of a camptothecin drug and a targeting moiety of the formula:
- TM-[L3]-[L2]-[L1]mAAn-CPT, where TM is a cancer -targeting moiety selected from the group consisting of a murine, chimeric, primatized, humanized, and human monoclonal antibody (MAb), and said antibody is an intact antibody, an antibody fragment selected from the group consisting of Fab, Fab′, F(ab)2 and F(ab′)2, or a single-chain antibody;
- CPT is camptothecin or an analog thereof;
- L3 is a component of a cross-linker comprising a cyclohexane linked antibody-coupling moiety;
- L2 comprises a defined PEG with 1-12 monomeric units attach to L3 at one end with a triazole moiety, is attached to L1 at the other end by an amide, hydrazide, carbonate or ester bond, or to CPT by a carbonate bond when L1 and AA are absent, or attached to AA by an amide bond when L1 is absent;
- L1 comprises a collapsible linker, or a peptidase-cleavable moiety optionally attached to a collapsible linker, or an acid-cleavable moiety;
- AA is an amino acid;
- m is an integer with values of 0 or 1, and n is an integer with values of 0, 1, 2, 3, or 4;
- and when n is >1, the amino acids represented by AA can be the same or different;
- wherein the antibody or fragment thereof binds to a tumor-associated antigen (TAA).
The method according to claim wherein said CPT is SN-38.
A method for treating a cancer, comprising administering a pharmaceutical composition to a subject, wherein the composition comprises a conjugate of a camptothecin drug and a targeting moiety of a formula selected from the group consisting of MAb-CL1-SN-38, MAb-CL2-SN-38, MAb-CL3-SN-38, MAb-CL4-SN-38, MAb-CL5-SN-38 and having a structure selected from:
- wherein the antibody or fragment thereof binds to a tumor-associated antigen (TAA).
The method according to 23, wherein the 10-hydroxy position of SN-38 is protected as 10-O-ester or 10-O-carbonate derivative using a ‘COR’ moiety where the R group is selected from substituted alkyl residue “N(CH3)2—(CH2)n—”where n is 2-10 and wherein the terminal amino group is optionally in the form of a quaternary salt for enhanced aqueous solubility, or simple alkyl residue “CH3—(CH2),—” where n is 0-10, or alkoxy residues “CH3—(CH2)n-O—” where n is 0-10 or “N(CH3)2—(CH2)n—O—” where n is 2-10, or “R1O—(CH2—CH2—O)n-CH2-CH2—O—” where R1 is ethyl or methyl and n is an integer with values of 0-10.
A method for treating an HIV infection, comprising administering a pharmaceutical composition to a subject with an HIV infection, wherein the composition comprises a conjugate of a camptothecin drug and a targeting moiety of the formula:
- TM-[L3]-[L2]-[L1]mAAn-CPT, where TM is an HIVgp120-targeting moiety selected from the group consisting of a murine, chimeric, primatized, humanized, and human monoclonal antibody (MAb), and said antibody is an intact antibody, an antibody fragment selected from the group consisting of Fab, Fab', F(ab)2 and F(ab')2, or a single-chain antibody CPT is camptothecin or an analog thereof;
- L3 is a component of a cross-linker comprising a cyclohexane linked antibody-coupling moiety;
- L2 comprises a defined PEG with 1-12 monomeric units attach to L3 at one end with a triazole moiety, is attached to L1 at the other end by an amide, hydrazide, carbonate or ester bond, or to CPT by a carbonate bond when L1 and AA are absent, or attached to AA by an amide bond when L1 is absent;
- L1 comprises a collapsible linker, or a peptidase-cleavable moiety optionally attached to a collapsible linker, or an acid-cleavable moiety;
- AA is an amino acid;
- m is an integer with values of 0 or 1, and n is an integer with values of 0, 1, 2, 3, or 4;
- and when n is >1, the amino acids represented by AA can be the same or different.
A method for treating an HIV infection, comprising administering a pharmaceutical composition to a subject with an HIV infection, wherein the composition comprises a conjugate of a camptothecin drug and a targeting moiety of a formula selected from the group consisting of MAb-CL1-SN-38, MAb-CL2-SN-38, MAb-CL3-SN-38, MAb-CL4-SN-38, MAb-CL5-SN-38 and having a structure selected from:
- wherein the antibody or fragment thereof binds to HIV gp 120.
Dependencies are inferred from the claim text.