Cyclodextrin Protein-Drug Conjugates for Stable Lipophilic Payload Delivery
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face challenges with lipophilic payloads that affect delivery efficiency and stability, leading to off-target side effects and reduced therapeutic index, necessitating improved modulation of linker properties and bioavailability.
Innovation Solution
Development of cyclodextrin-including protein-drug conjugates, where cyclodextrins are used to covalently link with payloads and proteins via linkers, enhancing delivery efficiency and stability, particularly for lipophilic payloads, thereby improving therapeutic index and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If lipophilic payloads are used in ADCs, then therapeutic potency is improved, but delivery efficiency and stability deteriorate
Solution Approach 1:
Cyclodextrins serve as intermediary molecules that contain the lipophilic payload within their hydrophobic cavity, shielding it from the aqueous environment. This mediator approach allows the payload to maintain its lipophilic potency while the cyclodextrin exterior provides water solubility and stability, resolving the contradiction between therapeutic potency and delivery stability
2Reliability
If lipophilic payloads are used in ADCs, then therapeutic potency is improved, but off-target side effects increase
Solution Approach 1:
The cyclodextrin acts as a protective intermediary that confines the lipophilic payload, preventing premature interaction with off-target cells. The payload is only released when the ADC is internalized by the target cell through antibody-antigen binding, thereby maintaining potency while reducing off-target toxicity
Solution Approach 2:
The lipophilic payload is nested within the cyclodextrin cavity, creating a hierarchical structure where the payload is protected inside the cyclodextrin shell. This nesting prevents the payload from interacting with the external environment until the appropriate release conditions are met at the target site
3Stability of the object's composition
If polar groups are added to linkers to reduce aggregation, then physiochemical properties improve, but linker complexity increases
Solution Approach 1:
Instead of modifying the linker structure with polar groups, the invention changes the parameter of the payload environment by enclosing it in cyclodextrin. This parameter change (from exposed lipophilic to shielded hydrophobic) improves solubility and reduces aggregation without requiring complex linker modifications
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The cyclodextrin-including protein-drug conjugates enhance the delivery and stability of lipophilic payloads, improving therapeutic efficacy and reducing off-target side effects, particularly for diseases like metabolic, proliferative, and neurodegenerative conditions.
Implementation Method 1
Cyclodextrins (CDs) are biodegradable soluble dietary fiber and food ingredients, and are also used as drug carriers. Their safety has been documented. CDs are more soluble than PEGs, and they have no charge like sulfonates
Implementation Method 2
a protein linked to at least one payload moiety and linked to at least one cyclodextrin moiety via a covalent linker, wherein said covalent linker is bonded directly or indirectly to each of the binding agent, the payload moiety, and the cyclodextrin moiety
Data Source
AI summary
Provided herein are compounds, compositions, conjugates and methods for the treatment of diseases, and/or conditions such as, but not limited to, proliferative diseases. In certain embodiments, compounds, compositions, and conjugates are provided, which include cyclodextrin-based linker-payloads and protein conjugates thereof, and/or in combination with other agents. By administering these compounds, compositions, and conjugates as described herein to specific target cells, side-effects due to non-specific binding phenomena, for example, to non-target cells are reduced.