Anticarcinogenic chemotherapeutic agents linked to an insulin-like growth factor-1 (IGFR-1) ligand; IGFR-1 is a variant having reduced binding affinity for soluble binding proteins compared to the wild-type; drugs/biological conjugates/; potentiation; side effect reduction
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Publication Number
US-7811982-B2
Publication Date
2010-10-12
Expiration Date
Abstract
The present invention provides a method of treating cancer involving administering an insulin-like growth factor-1 receptor (IGF-1 receptor) agonist and an anti-cancer chemotherapeutic agent. Also provided are compounds for treating cancer comprising an IGF-1-receptor ligand coupled to an anti-cancer chemotherapeutic agent. Also provided are compounds for treating cancer comprising an insulin-receptor ligand coupled to an anti-cancer chemotherapeutic agent.
Core Innovation
The invention relates to cancer treatment using a compound that comprises an anti-cancer chemotherapeutic agent linked to an insulin-like growth factor-1 (IGF-1) receptor ligand. The IGF-1 receptor ligand is a variant IGF-1 having reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1.
In the described embodiments, the IGF-1 receptor ligand variant is defined by specific sequence information, including the polypeptide structure A1-A2-A3-A4-LCG-A5-A6-LV-A7-AL-A8-A9-R1 and corresponding sequence IDs, with R1 defined as SEQ ID NO:6, and with a limitation that the variant IGF-1 does not consist of SEQ ID NO:1 or comprises SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10. The constructs are thus constrained to IGF-1 variants characterized by reduced binding affinity to soluble IGF-1 binding proteins.
The description further characterizes the cancer-treatment approach by stating that IGF-1 receptor targeting is used to enhance chemotherapy selectivity and potency, including potentiation via receptor-driven tumor cell division and/or increased receptor-mediated uptake via receptor-ligand-drug conjugates. Chemotherapeutic agents can be linked to insulin receptor ligands or IGF-1 receptor ligands, including non-insulin ligands, and the document includes representative conjugate embodiments with named anti-cancer chemotherapeutic agents linked to insulin, IGF-1, or IGF-2-related ligand entities.
The description also states coupling and linkage strategies between drug and receptor ligand, including hydrolyzable or cleavable linkages and a range of linkage chemistries such as carbodiimides/NHS activation, Schiff base, and disulfide linkages. It also presents chemical structures supporting the cross-linking and conjugation approaches described for forming the drug-protein conjugates.
Claims Coverage
The document includes two independent claim sets. Both cover cancer-treatment compounds defined by linking an anti-cancer chemotherapeutic agent to an IGF-1 receptor ligand that is a reduced-binding variant IGF-1 relative to wild-type for soluble IGF-1 binding proteins, with further definition by specific sequences in one set.
IGF-1R-ligand linked chemotherapeutic cancer compound with reduced soluble binding protein affinity variant
A compound for treating cancer comprising an anti-cancer chemotherapeutic agent linked to an insulin-like growth factor-1 (IGF-1) receptor ligand, wherein the IGF-1 receptor ligand is a variant IGF-1 that has reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1.
Specified IGF-1 variant polypeptide structure and exclusion of SEQ ID NO:1
The variant IGF-1 comprises the polypeptide structure A1-A2-A3-A4-LCG-A5-A6-LV-A7-AL-A8-A9-R1, wherein A1 is FV; A2 is N; A3 is Q; A4 is H; A5 is S; A6 is H; A7 is E; A8 is Y; A9 is L; and R1 is SEQ ID NO:6, provided the variant IGF-1 does not consist of SEQ ID NO:1.
IGF-1 variants defined by specific SEQ ID numbers linked to chemotherapeutic agent for cancer treatment
A compound for treating cancer comprising an anti-cancer chemotherapeutic agent linked to an insulin-like growth factor-1 (IGF-1) receptor ligand, wherein the IGF-1 receptor ligand is a variant IGF-1 that has reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1, wherein the variant IGF-1 comprises SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10.
Overall claim coverage centers on cancer-treatment compounds where an anti-cancer chemotherapeutic agent is linked to an IGF-1 receptor ligand that is a reduced-affinity IGF-1 variant for soluble IGF-1 binding proteins, with additional structural or sequence identity constraints defining the variant IGF-1.
Stated Advantages
enhance chemotherapy selectivity
enhance chemotherapy potency
potentiation via receptor-driven tumor cell division
increased receptor-mediated uptake via receptor-ligand-drug conjugates
side effect reduction
Documented Applications
Treating cancer using a compound comprising an anti-cancer chemotherapeutic agent linked to an insulin-like growth factor-1 (IGF-1) receptor ligand.
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