Folate receptor binding conjugates of antifolates
Conjugates of antifolates, releasable linkers, and drugs, and pharmaceutical compositions containing them are described. The conjugates are useful for treating diseases arising from pathogenic cell populations. Methods for treating such diseases are also described.
1. A conjugate of the formula ALD m wherein A is an antifolate; L is a linker comprising at least one releasable linker; m is 1 to about 3; and each D is an independently selected drug, wherein the antifolate is of the formula
2. The conjugate of claim 1 wherein m is 1 or 2.
3. The conjugate of claim 1 wherein m is 1.
4. The conjugate of claim 1 wherein the linker comprises at least one releasable linker that is not a disulfide.
5. The conjugate of claim 1 wherein the linker comprises at least two releasable linkers.
6. The conjugate of claim 5 wherein at least one releasable linker is not a disulfide.
7. The conjugate of claim 1 wherein at least one D is selected from the group consisting of vinca alkaloids, tubulysins, mitomycins, and epothilones.
8. A pharmaceutical composition comprising the conjugate of claim 1 , and one or more carriers, excipients, or diluents, or combinations thereof.
9. A method for treating a population of pathogenic cells in a patient, the method comprising administering a therapeutically effective amount of the conjugate of claim 1 , or a composition thereof comprising one or more carriers, excipients, or diluents, or combinations thereof, to the patient, wherein the pathogenic cells uniquely express, preferentially express, or over-express folate receptors.
10. The method of claim 9 wherein the pathogenic cells are cancer cells.
11. The method of claim 10 , wherein the conjugate binds to a folate receptor on the cancer cell and upon binding is internalized into the cancer cell.