Back to Search
Start Over
Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy
- Source :
- Protein engineering, designselection : PEDS. 30(12)
- Publication Year :
- 2017
-
Abstract
- Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy.
- Subjects :
- 0301 basic medicine
Male
medicine.drug_class
Cell
Bioengineering
Monoclonal antibody
Biochemistry
03 medical and health sciences
Prostate cancer
Cell Line, Tumor
LNCaP
Antibodies, Bispecific
medicine
Humans
Receptor
Molecular Biology
Cell Nucleus
biology
Chemistry
Prostatic Neoplasms
Ligand (biochemistry)
medicine.disease
Androgen receptor
030104 developmental biology
medicine.anatomical_structure
Receptors, Androgen
Cancer research
biology.protein
Antibody
Biotechnology
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 17410134
- Volume :
- 30
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Protein engineering, designselection : PEDS
- Accession number :
- edsair.doi.dedup.....58d4d1cc819ccc3566f6a929e54dc234