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Publication Number
US-11130730-B2
Publication Date
2021-09-28
Expiration Date
Abstract
The invention relates to novel compounds with the ability to link an immune response to a defined therapeutic target, to the use of said compounds in treating cancer and infectious diseases, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
Core Innovation
The patent describes compounds of formula (I) or pharmaceutically acceptable salts that combine a nucleic acid aptamer binding moiety (L) with multiple spacer segments (S1, S2, S3) and linkage groups (X1, Y1, Y2). The framework further includes a carbohydrate molecule (F) capable of binding to a human anti-alpha-galactosyl antibody, together with aromatic groups CyA, CyB and CyC. The spacer segments are defined by selectable chain lengths and optional substitutions, using variable integer parameters and defined bond and linkage options.
The patent also describes modular immuno-linker therapeutic compounds in which the structure is configured to control the number and position of the F groups relative to L. The carbohydrate includes alpha-galactosyl-related saccharides, and the aptamer binding moiety includes targets such as EGFR, PSMA, and Pseudomonas aeruginosa binding nucleic acid aptamers. The described concept uses rigid cyclic phenyl, biphenyl, and triphenyl scaffolds in the immuno-linker design.
The described work supports scaffold assembly of large glyco-conjugate architectures aligned with the claimed aptamer, spacer, and carbohydrate targeting framework. The partial content includes preparation of protected and integrated linker and carbohydrate-containing constructs, characterization of key intermediates and final constructs, and a final hydrogenated or bottom-up assembled multivalent cluster referred to as a Double Cluster species. Overall, the described assembly and characterization support the construction of the targeted multivalent aptamer, spacer, and carbohydrate compound architecture.
Claims Coverage
The provided independent claims cover modular compound structures defined by formula (I), formula (I)a, and formula (II), each combining a nucleic acid aptamer binding moiety (L) with a carbohydrate (F) that binds human anti-alpha-galactosyl antibodies, using multiple spacer and linkage modules and aromatic cores. Across the inputs, there are 4 inventive feature groupings that recur in the independent claims and related claim definitions.
Modular immuno-linker compound of formula (I)
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L represents a binding moiety selected from a nucleic acid aptamer; S1, S2, and S3 represent selected spacer structures with defined optional substituents and integer ranges; X1 represents —O—; Y1 and Y2 independently represent selected bond or linkage groups; F represents a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody; m1 and m2 are selected from defined integers; n is selected from 1 or 2; and CyA, CyB and CyC independently represent biphenyl or triphenyl.
Parametrized compound of formula (I)a
A compound of formula (I)a or a pharmaceutically acceptable salt thereof, wherein L represents a binding moiety selected from a nucleic acid aptamer; S1 is selected as a —(CH2)a— group with a fixed integer a; S2 and S3 are selected spacer groups with restricted integer selections and optional substitutions as defined; X1 represents —O—; Y1 and Y2 independently represent —O— or —C(O)NH—; F represents a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody; m1 and m2 are selected from defined integers; n is fixed to 1; and CyA, CyB and CyC independently represent biphenyl or triphenyl.
Carbohydrate-containing compound of formula (II)
A compound of formula (II) wherein S2 and S3 are selected spacer groups with defined optional substitutions and integer ranges; Y2 is selected from defined bond or linkage groups; m1 and m2 are selected from defined integers; n is selected from 1 or 2; CyA, CyB and CyC independently represent biphenyl or triphenyl; and F represents a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody.
Preparation and interconversion of formula (I) compounds
A process for preparing a formula (I) compound comprising preparing a formula (I) compound where Y1 is —CONH— by reacting a formula (II) compound with a formula (III) compound using conditions (i), and/or interconverting a formula (I) compound or its protected derivative to another formula (I) compound or protected derivative.
The claim coverage centers on modular immuno-linker compounds that combine a nucleic acid aptamer binding moiety (L) with a carbohydrate (F) that binds human anti-alpha-galactosyl antibodies, implemented through selected spacer segments (S1-S3), linkage selections (X1, Y1/Y2, and/or Y2), and aromatic cores (CyA-CyC) selected as biphenyl or triphenyl, with additional restrictions expressed through defined integer ranges and optional substituent selections. The provided dependent-claim guidance narrows the carbohydrate F and the aptamer L to specific choices, and the claims also include preparation and interconversion of formula (I) compounds via specified intermediates and conditions.
Stated Advantages
Improved immune recruitment.
Easier and scalable synthesis.
Fewer chiral centers.
Reduced protease degradation.
Less labile or cleavable linker liability.
Documented Applications
Therapeutic use for cancer, including PSMA-mediated diseases and prostate cancer, tied to aptamer choice such as EGFR and PSMA-binding nucleic acid aptamers.
Therapeutic use for P. aeruginosa infections, including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), tied to a Pseudomonas aeruginosa/PA binding nucleic acid aptamer.
Therapeutic use in cystic fibrosis and coryneal infection.
Cancer therapy via an EGFR aptamer immuno-linker described in the document.
PSMA-mediated disease treatment using the described immuno-linker concept.
Prevention and/or treatment of Pseudomonas aeruginosa infection using the described immuno-linker concept, including associated clinical contexts.
Use in pharmaceutical compositions and formulation as described in the document, including phosphate salt and broad dosing ranges.
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