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Publication Number
US-9011880-B2
Publication Date
2015-04-21
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 concerns a method of treating cancer in a mammal by administering a compound comprising an anti-cancer chemotherapeutic agent linked to an insulin-like growth factor-1 (IGF-1) receptor ligand. The compound inhibits growth of the cancer in the mammal, where the cancer cells in the mammal have IGF-1 receptors. The IGF-1 receptor ligand is an IGF-1 receptor agonist that is a variant IGF-1 having reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1.
The reduced-soluble-binding-affinity variant IGF-1 is defined by a polypeptide structure A1-A2-A3-A4-LCG-A5-A6-LV-A7-AL-A8-A9-R1 with specified allowable amino-acid options, with R1 being SEQ ID NO:6, and with the condition that the variant IGF-1 does not consist of SEQ ID NO:1. Alternative definitions include variants comprising any one of SEQ ID NOS:4 and 7-11.
In the disclosed examples, IGF-1 receptor ligand conjugates are formed with multiple anti-cancer chemotherapeutic drugs, including methotrexate and doxorubicin, using carbodiimides and other cross-linkers. Competitive binding indicates tighter IGF-1R binding for the reduced-soluble-binding-affinity IGF-1 variant conjugate compared to unconjugated ligand, and the disclosed in vitro and in vivo results describe cancer growth inhibition and improved effectiveness at lower chemotherapeutic dosing.
Claims Coverage
The partial content identifies four independent claims. Across these independent claims, the inventive subject matter centers on linking an anti-cancer chemotherapeutic agent to an IGF-1 receptor agonist that is a reduced-soluble-binding-affinity IGF-1 variant and on treating IGF-1 receptor-positive cancer with dosage constraints relative to maximum safe cumulative dosage per 3 weeks.
IGF-1 receptor agonist reduced-soluble-binding-affinity IGF-1 variant linked to anti-cancer chemotherapeutic agent
Administering to the mammal a compound comprising an anti-cancer chemotherapeutic agent linked to an insulin-like growth factor-1 (IGF-1) receptor ligand, wherein the compound inhibits growth of the cancer in the mammal; wherein the IGF-1 receptor ligand is an IGF-1 receptor agonist that is a variant IGF-1 that has reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1; and wherein cancer cells in the mammal have IGF-1 receptors.
Defined reduced-soluble-binding-affinity IGF-1 variant by polypeptide structure and sequence exclusions
Wherein the variant IGF-1 with reduced binding affinity to the soluble IGF-1 binding proteins comprises the polypeptide structure A1-A2-A3-A4-LCG-A5-A6-LV-A7-AL-A8-A9-R1, wherein A1 is G, V, or FV; A2 is P or N; A3 is E or Q; A4 is T, H, or A; A5 is A or S; A6 is E or H; A7 is D or E; A8 is Q or Y; A9 is F or L; and R1 is SEQ ID NO:6; provided the variant IGF-1 does not consist of SEQ ID NO:1; or wherein the variant IGF-1 with reduced binding affinity to the soluble IGF-1 binding proteins comprises any one of SEQ ID NOS:4 and 7-11.
Not insulin IGF-1 receptor ligand with treatment dosing constraint
Wherein the IGF-1 receptor ligand is an IGF-1 receptor agonist that is a variant IGF-1 that has reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1; wherein the IGF-1 receptor ligand is not insulin; and wherein the compound is administered at a cumulative dosage per 3 weeks that is less than 50% of a maximum safe cumulative dosage per 3 weeks of the anti-cancer chemotherapeutic agent in the mammal.
Not insulin IGF-1 receptor ligand with higher-than-safe cumulative dosage constraint
Wherein the IGF-1 receptor ligand is an IGF-1 receptor agonist that is a variant IGF-1 that has reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1; wherein the IGF-1 receptor ligand is not insulin; and wherein the compound is administered at a cumulative dosage per 3 weeks that is more than a maximum safe cumulative dosage per 3 weeks of the anti-cancer chemotherapeutic agent in the mammal.
IGF-1 receptor-positive cancer treatment with single-dose and maximum-safe cumulative dosage constraints
Wherein the IGF-1 receptor ligand is an IGF-1 receptor agonist that is a variant IGF-1 that has reduced binding affinity for soluble IGF-1 binding proteins compared to wild-type IGF-1; wherein the IGF-1 receptor ligand is not insulin; wherein the compound is administered in a single dose that is less than 20% of a maximum safe cumulative dosage per 3 weeks of the anti-cancer chemotherapeutic agent; and wherein the compound is administered at a cumulative dosage per 3 weeks that is less than a maximum safe cumulative dosage per 3 weeks of the anti-cancer chemotherapeutic agent in the mammal; and wherein cancer cells in the mammal have IGF-1 receptors.
Across the independent claims, coverage is directed to treating IGF-1 receptor-positive cancer by administering a compound where an anti-cancer chemotherapeutic agent is linked to a not-insulin IGF-1 receptor agonist variant with reduced binding affinity for soluble IGF-1 binding proteins. The claims define acceptable IGF-1 variant forms by a specified polypeptide structure and sequence/SEQ ID exclusions or inclusions, and further constrain treatment by dosage relationships to maximum safe cumulative dosage per 3 weeks, including specific single-dose and relative dosage fractions.
Stated Advantages
Cancer growth inhibition.
Improved effectiveness at lower chemotherapeutic dosing.
Tighter IGF-1R binding for the reduced-soluble-binding-affinity IGF-1 variant conjugate compared to unconjugated ligand.
Documented Applications
Treatment of cancer in a mammal having IGF-1 receptor-positive cancer cells.
In vitro and in vivo evaluation of cancer growth inhibition.
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