Stable and Potent Selenomab-Drug Conjugates

Xiuling Li; Christopher G Nelson; Rajesh R Nair; Lori Hazlehurst; Tina Moroni; Pablo Martinez-Acedo; Alex R Nanna; David Hymel; Terrence R Burke Jr; Christoph Rader

doi:10.1016/j.chembiol.2017.02.012

Stable and Potent Selenomab-Drug Conjugates

Cell Chem Biol. 2017 Apr 20;24(4):433-442.e6. doi: 10.1016/j.chembiol.2017.02.012. Epub 2017 Mar 16.

Authors

Affiliations

¹ Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
² Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
³ Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
⁴ Proteomics and Mass Spectrometry Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
⁵ Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: [email protected].

Abstract

Selenomabs are engineered monoclonal antibodies with one or more translationally incorporated selenocysteine residues. The unique reactivity of the selenol group of selenocysteine permits site-specific conjugation of drugs. Compared with other natural and unnatural amino acid and carbohydrate residues that have been used for the generation of site-specific antibody-drug conjugates, selenocysteine is particularly reactive, permitting fast, single-step, and efficient reactions under near physiological conditions. Using a tailored conjugation chemistry, we generated highly stable selenomab-drug conjugates and demonstrated their potency and selectivity in vitro and in vivo. These site-specific antibody-drug conjugates built on a selenocysteine interface revealed broad therapeutic utility in liquid and solid malignancy models.

Keywords: antibody-drug conjugates; cancer therapy; selenocysteine; site-specific conjugation.

MeSH terms

Animals
Antibodies, Monoclonal / chemistry*
Antibodies, Monoclonal / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Breast Neoplasms / drug therapy
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Survival / drug effects
Female
Fluorescein / chemistry
Humans
Immunoconjugates / blood
Immunoconjugates / chemistry
Immunoconjugates / metabolism*
Interleukin Receptor Common gamma Subunit / immunology
Interleukin Receptor Common gamma Subunit / metabolism
Mice
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Pharmaceutical Preparations / chemistry*
Protein Stability
Receptor, ErbB-2 / immunology
Receptor, ErbB-2 / metabolism
Selenocysteine / chemistry
Selenocysteine / immunology
Selenocysteine / metabolism
Syndecan-1 / immunology
Syndecan-1 / metabolism
Transplantation, Heterologous

Substances

Antibodies, Monoclonal
Antineoplastic Agents
Immunoconjugates
Interleukin Receptor Common gamma Subunit
Pharmaceutical Preparations
Syndecan-1
Selenocysteine
Receptor, ErbB-2
Fluorescein

Abstract

MeSH terms

Substances

Grants and funding