Cleavable conjugates of TLR7/8 agonist compounds, methods for preparation, and uses thereof
Inventors
Coffman, Robert L. • Chipman, Stewart D. • Kiwan, Radwan • Zalipsky, Samuel • Ott, Gary S.
Assignees
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Publication Number
US-10722591-B2
Publication Date
2020-07-28
Expiration Date
Abstract
The present disclosure relates to cleavable conjugates (for example, particle-based or antibody-based conjugates) of TLR7/8 agonists (for example, 1H-imidazo[4,5-c]quinoline derivatives) containing a conjugation linker, a cleavable linker, and a self-eliminating linker. The present disclosure also related to methods for preparation of the cleavable conjugates, uses thereof for stimulating an effective immune response, and uses thereof for the treatment of cancer.
Core Innovation
The invention concerns compounds of formula (I) in which D is a TLR7/8 agonist moiety and the TLR7/8 agonist moiety is a 1H-imidazo[4,5-c]quinoline derivative. The compound includes a self-eliminating linker L1, a cleavable linker L2, and a conjugation linker L3, with W as O, S, or N, R10 as H or C1-C8 alkyl, and x as an integer from 1 to 500. The conjugation moiety F is included in the overall scaffold.
The disclosed scaffold combines the 1H-imidazo[4,5-c]quinoline-based TLR7/8 agonist moiety with linker elements that define attachment and cleavage behavior within formula (I). The linker architecture is described as W-L3-L2-L1-D, and the conjugation moiety F is connected through the conjugation linker region. Dependent refinements define specific D structures, including formulae D-2a, D-2b, D-4a, and D-4b, with variable substituents on the imidazo[4,5-c]quinoline core.
The cleavable linker L2 is described as being cleavable by one or more endosomal or lysosomal peptidase(s)/protease(s) and/or one or more pericellular peptidase(s)/protease(s) expressed by cells in the tumor microenvironment. Named options include Cathepsin B, uPA, matriptase, matriptase-2, and legumain. The conjugation moiety F is described in examples as particle-based, branched copolymer of sucrose and epichlorohydrin, dendrimer, Ficoll-type, polypeptide antigen, or antibody-based conjugation moiety.
Claims Coverage
The independent claim is clm-00001. It defines one formula (I) scaffold with a 1H-imidazo[4,5-c]quinoline TLR7/8 agonist moiety and three linker roles, and the dependent claims refine the D moiety, linker cleavage dependencies, and conjugation moiety F forms.
TLR7/8 agonist moiety as a 1H-imidazo[4,5-c]quinoline derivative
D is a TLR7/8 agonist moiety, and the TLR7/8 agonist moiety is a 1H-imidazo[4,5-c]quinoline derivative.
Self-eliminating linker, cleavable linker, and conjugation linker architecture
L1 is a self-eliminating linker, L2 is a cleavable linker, and L3 is a conjugation linker.
Formula (I) scaffold with defined attachment variables
W is O, S, or N, R10 is H or C1-C8 alkyl, x is an integer from 1 to 500, and F is a conjugation moiety.
Cleavable linker L2 defined by protease cleavage dependency
L2 is cleavable by one or more endosomal or lysosomal peptidase(s)/protease(s) and/or one or more pericellular peptidase(s)/protease(s) expressed by cells in the tumor microenvironment.
The claim coverage centers on a formula (I) compound that combines a 1H-imidazo[4,5-c]quinoline TLR7/8 agonist moiety D with a self-eliminating linker L1, a cleavable linker L2, and a conjugation linker L3, together with defined W, R10, and x variables and a conjugation moiety F.
Stated Advantages
Supports cleavage-triggered release of the unconjugated TLR7/8 agonist moiety D.
Supports tumor accumulation/retention in conjunction with cleavage-triggered D release.
Reduces systemic pro-inflammatory cytokines while stimulating effective anti-cancer immune responses.
Maintains reduced agonist activity until cleavage of L2 in the tumor microenvironment.
Documented Applications
Use in tumor microenvironment contexts to support cleavage of the linker and release of the unconjugated TLR7/8 agonist moiety D.
Treatment of cancer and immune stimulation via compounds that release/stabilize activity in the tumor microenvironment.
Conjugation formats intended to support tumor accumulation/retention.
Tumor microenvironment cleavage of L2.
Synthetic preparations for Ficoll-PACM conjugate compounds, including Compound 64-54a, Compound 64-54b, and Compound 64-54c.
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