New Click Chemistry for Antibody Drug Conjugates (ADCs) production
We propose a solution for producing ADCs by click chemistry which uses a specific linker allowing a conjugation on solid support and a more efficient liberation of the compounds.
Benefits
- Conception of the “object” using a solid support that simplify synthesis and purification processes
- Fully reproducible and robust approach
- Purification steps are replaced by filtrations
- Better effectiveness in scaling, kinetic
- Cost effective solution
- Versatile building block proposal
- Improved linker reactivity for better liberation strategy
Issue
Current ADCs click chemistry syntheses are based on conjugation strategy using a linker in homogenous phase. They need two “click” operations, one for the drug and one for the antibody, each of them followed by a complex purification (Cf figure 1a on third illustration). These syntheses are using mostly the BCN linker for Strain Promoted Alkyne Azide cycloadditions (SPAAC) (Cf figure 1b).
These approaches have several drawbacks:
Concerning the process:
- It is operated in solution which complexifies purification phases and may cause difficulties of reproducibility
- It requires two steps of purification after each “click”, the one addressing antibody clicking being quite complex
- Duration of the process
Concerning the BCN linker, its structure implies:
- Longer time of reaction due to its moderate reactivity
- Prevent any strategy of liberation of the antibody from conjugates or solid support
Solution
We develop a linker based on Cycloheptine-dicobaltcarbonyl complexes (Cf figure 2a on main illustration above), which can be used in orthogonal/sequential linking reactions such as orthogonal SPAAC and Copper catalyzed Alkyne Azyde Cycloadditions (CuAAC - Cf figure 2c). Such configuration of linkers, with improved reactivity, allows the use of solid support during the synthesis and drastically improved liberation strategies.
We are currently developing a conjugation strategy using a linker on solid support that will optimize/simplify the process by replacing purification steps by simple filtrations (Cf figure 2b).
Important remark: the linker can be bespoke to requested “click reaction”, thus, with or without cycloheptyne-dicobalt carbonyl complexes"