Diazido macrocyclic sulfates as a platform for the synthesis of sequence-defined polymers for antibody drug conjugates. Issue 13 (14th March 2022)

• Record Type: Journal Article
• Authors: Forsythe, Neil L.; Tan, Mikayla F.; Maynard, Heather D.
• Is Part Of: Chemical science. Volume 13:Issue 13(2022)
• Page Start: 3888
• Page End: 3893
• Publication Date: 2022-03-14
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc06242e
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : We report a new method for the synthesis of functional, sequence-defined polyethers and apply the material to antibody conjugation. Abstract : To improve the efficacy of antibody drug conjugates (ADCs), there has been significant focus on increasing the drug-to-antibody ratio (DAR) in order to deliver more payload. However, due to the hydrophobicity of many cytotoxics, highly-loaded conjugates often have lower physicochemical stability and poorer pharmacokinetic outcomes, requiring the development of new hydrophilic linkers. Herein, we report a platform for the preparation of functional, sequence-defined polymers for conjugation to antibodies. We demonstrate the successful synthesis of novel diazido macrocyclic sulfate monomers of varied size ranging from 4 to 7 ethylene glycol repeat units. These monomers were then successively ring-opened to produce sequence-defined polymers that contained either 4 or 6 azides for post-synthesis functionalization. Given the hydrophilic ethylene glycol backbone and chemically defined nature of the polymers, we envisioned this as a useful strategy in the preparation of highly-loaded ADCs. To demonstrate this, we prepared a model polymer-fluorophore scaffold composed of 4 coumarin molecules and conjugated it to Herceptin. We fully characterized the conjugate via mass spectrometry, which yielded a polymer-to-antibody ratio of 6.6, translating to a total of 26 fluorophores conjugated to the antibody at the inter-chain disulfides. We believe this technology to not only be a meaningful contribution to the field of sequence-defined polymers and conjugates, but also as a general and tunable platform for drug delivery.