New Click Chemistry for Antibody Drug Conjugates (ADCs) production

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

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"