Imidazoquinoline Immunomodulators with C-7 Ester Groups
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Solution Overview
Problem
Current imidazoquinoline-based compounds used as vaccine adjuvants induce a suboptimal ratio of pro-inflammatory to anti-inflammatory cytokines, limiting their immunogenic potential and systemic immunity, particularly in cancer vaccines where TLR7 and TLR8 agonists are suboptimally effective unless directly conjugated to antigens.
Innovation Solution
Development of imquidazolequinoline-based compounds that trigger a more desirable cytokine profile by incorporating an ester group at C-7, activating inflammatory cytokine responses even in the absence of TLR7 or TLR8 agonist activity, and optimizing cytokine production, including IL-1β activation, to enhance immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If imiquimod or resiquimod is used as a vaccine adjuvant, then TLR7 and TLR8 signaling is activated, but the ratio of pro-inflammatory to anti-inflammatory cytokines remains suboptimal, limiting immunogenic potential
Solution Approach 1:
The patent modifies the chemical structure of imidazoquinoline compounds by introducing specific substitutions at the C-7 position (such as ester groups) to change the pharmacological parameters of the molecule. These structural parameter changes result in altered cytokine production profiles, specifically enhancing pro-inflammatory cytokine responses while reducing anti-inflammatory cytokine production, thereby optimizing the pro- to anti-inflammatory cytokine ratio for improved vaccine adjuvanticity.
2Reliability
If TLR ligand and antigen are co-administered as a mixture, then APCs may engulf both components, but signal to noise ratio is reduced due to separate uptake
Solution Approach 1:
The patent employs covalent conjugation to merge the TLR ligand and antigen into a single molecular entity. This merging ensures that when antigen-presenting cells engulf the conjugate, both the TLR signaling component and the antigen are internalized together in the same endosome, guaranteeing synchronized delivery and eliminating the signal to noise problems associated with separate administration. The conjugate structure physically links the immunostimulatory TLR ligand with the antigen, ensuring co-uptake and co-presentation.
Solution Approach 2:
The patent uses a linker molecule as an intermediary to connect the TLR ligand and antigen. This intermediary component facilitates the stable covalent bonding between the two components while allowing for controlled release or processing within the antigen-presenting cell. The linker serves as a mediator that maintains the integrity of the conjugate structure during circulation and delivery, while enabling the biological functions of both the TLR ligand and antigen upon cellular uptake.
3Reliability
If imiquimod is used topically, then local immune response is stimulated, but systemic immunity is impaired due to high IL-10 production
Solution Approach 1:
The patent introduces structural modifications to imidazoquinoline compounds, specifically adding substituents at the C-7 position such as ester groups, which fundamentally change the cytokine production parameters of the molecule. These parameter changes result in a shifted cytokine profile that reduces IL-10 production while enhancing pro-inflammatory cytokine output, thereby maintaining local immune stimulation while preventing the systemic immunosuppression associated with parent compounds like imiquimod and resiquimod.
Data Source
AI summary
The invention provides compounds of formula I: wherein R1-R3, Ra, and Rb have any of the values defined herein, and salts thereof. The compounds have immunomodulatory properties.