Antibody-STING agonist conjugates and their use in immunotherapy
Inventors
Chen, Zhijian • Shi, Heping • Wei, Qi • Chen, Chuo • Sun, Lijun • Qiu, Jian • WU, Youtong
Assignees
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Publication Number
US-11033635-B2
Publication Date
2021-06-15
Expiration Date
Abstract
The present disclosure relates to, among other things, antibody-drug conjugates comprising a STING agonist cyclic di-nucleotide conjugated to an antibody, preparation methods therefor, and uses therefor.
Core Innovation
The invention relates to antibody-drug conjugates (ADCs) in which the drug payload (D) is a cyclic di-nucleotide (CDN) covalently bound to a linker (L). The ADC has a structure defined by Formula Ia, where Ab represents an antibody or binding fragment that binds a target antigen, and L links one or more occurrences of D to Ab. The CDN is covalently bound to linker (L) at the amino, or C1-6 alkylamino group at the R1 position of the CDN.
The drug payload D is a cyclic di-nucleotide having the structure of Formula IIk, with W, X, Y, and Z independently being CH or N. The R1 substituent is C2-4 alkyl substituted with an amino or C1-6 alkylamino group, and the RP substituent is independently hydroxyl, thiol, C1-6 alkyl, —BH3, or —NR′R″, where R′ and R″ are hydrogen or C1-6 alkyl optionally substituted with groups selected from multiple listed substituents, or where R′ and R″ on the same nitrogen form a C3-5 heterocyclic ring.
The invention also covers compounds of Formula IIk defined by the CDN structure, including pharmaceutically acceptable salts. The disclosure further describes cleavable versus non-cleavable linker chemistry, including carbonate coupling represented as L-OC(O)O-CDN and disulfide coupling represented as L-S-S-CDN.
Claims Coverage
The independent claim set includes 2 independent claims: an ADC of Formula Ia and a compound of Formula IIk. Across these claims, the inventive coverage focuses on the covalent CDN payload chemistry, the defined structural variables of the CDN, and the ADC linkage concept connecting the CDN-containing linker to an antibody binding a target antigen.
Antibody-drug conjugate with cyclic di-nucleotide payload covalently bound at R1 amino or C1-6 alkylamino
An ADC having the structure of Formula Ia, where D is a cyclic di-nucleotide (CDN) of Formula IIk covalently bound to linker (L) at the amino, or C1-6 alkylamino group at the R1 position, and the linker links one or more occurrences of D to an antibody Ab or binding fragment that binds a target antigen.
CDN compound defined by Formula IIk
A compound of Formula IIk where W, X, Y, and Z are independently CH or N, R1 is ethyl substituted with an amino or C1-6 alkylamino group, and RP is hydroxyl, thiol, C1-6 alkyl, —BH3, or —NR′R″ with R′ and R″ being hydrogen or C1-6 alkyl optionally substituted with the listed groups, or where R′ and R″ on the same nitrogen together form a C3-5 heterocyclic ring; including a pharmaceutically acceptable salt thereof.
Overall claim coverage is directed to ADCs featuring a linker-connected antibody targeting a target antigen, where the attached payload is a structurally defined cyclic di-nucleotide covalently connected to the linker at a specified R1 functional group position, and to the corresponding structurally defined CDN compounds of Formula IIk (including pharmaceutically acceptable salts).
Stated Advantages
Improved local exposure in the tumor.
Reduced systemic cytokine side effects by avoiding systemic cytokine leakage.
Documented Applications
Cancer immunotherapy and immune-response, including interferon-β2 (IFNβ2), checkpoint inhibitor synergy, and delivery via STING agonism using ADC (Formula I) and/or free CDN (Formula II).
Pharmaceutical compositions and medicaments containing the described ADCs and/or CDNs.
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