Structural highlights
Function[CD38_HUMAN] Synthesizes cyclic ADP-ribose, a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activity. Also moonlights as a receptor in cells of the immune system. Publication Abstract from PubMedMost of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate-ribosyl cyclase-enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties. Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases.,Dai Z, Zhang XN, Nasertorabi F, Cheng Q, Li J, Katz BB, Smbatyan G, Pei H, Louie SG, Lenz HJ, Stevens RC, Zhang Y Sci Adv. 2020 Jun 3;6(23):eaba6752. doi: 10.1126/sciadv.aba6752. eCollection 2020, Jun. PMID:32537509[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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