CC-1065 analogs and their conjugates
Inventors
Beusker, Patrick Henry • Coumans, Rudy Gerardus Elisabeth • Elgersma, Ronald Christiaan • Menge, Wiro Michael Petrus Bernardus • Joosten, Johannes Albertus Frederikus • Spijker, Henri Johannes • De Groot, Franciscus Marinus Hendrikus
Assignees
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Publication Number
US-9815784-B2
Publication Date
2017-11-14
Expiration Date
Abstract
This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
Core Innovation
The invention relates to compounds of formula (III) and pharmaceutically acceptable salts thereof, wherein V2 is a full-length antibody or an antigen-binding fragment thereof. The structure further comprises linking groups L2 and L that connect V2 to one or more V1 and/or Y, and each V1 is a conditionally-cleavable or conditionally-transformable moiety that can be cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process.
The construct includes Y as a self-eliminating spacer system comprised of one or more self-elimination spacers, linked to V1, optionally L, and one or more Z. Each Z is a compound of formula (I) with R1 as a leaving group selected as Cl, and Z is connected to Y through X1 or through an atom bearing specified substituents.
The framework defines p and q as positive integers representing a degree of branching, and z as a positive integer equal to or smaller than the total number of attachment sites for Z. The disclosed formulas further specify variable substitution constraints, including X2, R2, R2′, R4, R4′, R12, R19, DB selection, and water-soluble groups, together with DB1–DB9 and related structural variability within the overall antibody-linked linker-agent construct.
Claims Coverage
The independent claim coverage centers on an antibody-based formula (III) construct with 5 core inventive features.
Antibody-based formula (III) construct
A compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein V2 is a full-length antibody or an antigen-binding fragment thereof, and L2 and L are independently absent or linking groups that connect V2 to one or more V1 and/or Y.
Conditionally-cleavable or conditionally-transformable moiety V1
Each V1 is a conditionally-cleavable or conditionally-transformable moiety that can be cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process.
Self-eliminating spacer system Y
Each Y is independently absent or a self-eliminating spacer system comprised of one or more self-elimination spacers and linked to V1, optionally L, and one or more Z.
Branched attachment architecture
p and q are positive integers representing a degree of branching, and z is a positive integer equal to or smaller than the total number of attachment sites for Z.
Formula (I) Z units with leaving group Cl
Each Z is independently a compound of formula (I) wherein R1 is a leaving group selected as Cl, and each Z is connected to Y through X1 or through an atom bearing specified substituents, with additional constraints on X2, R2, R2′, R4, R4′, R12, R19, DB, and water-soluble groups.
The claim coverage centers on an antibody-linked formula (III) construct that combines V1, Y, and Z units under defined branching and connectivity rules, with Z defined by formula (I) and a chlorine leaving group. The disclosed scope also includes variable DB and substituent definitions, including water-soluble group options.
Stated Advantages
Improves water solubility.
Reduces aggregation.
Reduces side effects.
Favors electrostatic DNA binding with DNA phosphate groups.
Enhanced metabolic degradation (liver) and detoxification through oxidizable groups such as acetylene/alkene.
Improves DNA-binding affinity.
May provide a detoxification handle arising from oxidation/hydration of the double bond when ring B is connected through a vinyl group.
Improves binding/activation properties.
Improves pharmacokinetics.
Improves therapeutic index.
Enhances tumor selectivity.
Attaching L to V1 versus Y provides stability/solubility/aggregation advantages.
Documented Applications
A method for treating or preventing a tumor in a mammal by administering a pharmaceutical composition in a therapeutically effective dose.
Treating or preventing tumors in a mammal by administering a pharmaceutical composition in a therapeutically effective dose.
Administration of compositions containing the defined compounds for tumor and undesired cell proliferation.
Administration of compositions containing the defined compounds for inflammatory disease and autoimmune disease.
Administration of compositions containing the defined compounds for bacterial, viral, or other microbial infection.
Use in pharmaceutical manufacturing.
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