Stable and Potent Selenomab-Drug Conjugates.
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.
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
Xiuling
X
Li
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Christopher G
CG
Nelson
Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Rajesh R
RR
Nair
Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Lori
L
Hazlehurst
Proteomics and Mass Spectrometry Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
Tina
T
Moroni
Proteomics and Mass Spectrometry Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
Pablo
P
Martinez-Acedo
Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
Alex R
AR
Nanna
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
David
D
Hymel
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Terrence R
TR
Burke
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: crader@scripps.edu.
Christoph
C
Rader
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D019793:Fluorescein / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D055550:Protein Stability; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D017279:Selenocysteine / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D053668:Syndecan-1 / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019793:Fluorescein; D018796:Immunoconjugates; D053631:Interleukin Receptor Common gamma Subunit; D004364:Pharmaceutical Preparations; D018719:Erb-b2 Receptor Tyrosine Kinases; D017279:Selenocysteine; D053668:Syndecan-1
antibody-drug conjugates; cancer therapy; selenocysteine; site-specific conjugation