Cargando…

Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates

Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is...

Descripción completa

Detalles Bibliográficos
Autores principales: Nanna, Alex R., Li, Xiuling, Walseng, Even, Pedzisa, Lee, Goydel, Rebecca S., Hymel, David, Burke Jr., Terrence R., Roush, William R., Rader, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653646/
https://www.ncbi.nlm.nih.gov/pubmed/29062027
http://dx.doi.org/10.1038/s41467-017-01257-1
Descripción
Sumario:Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, this strategy affords the ability to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and non-Hodgkin lymphoma, respectively.