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A novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant
Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumors
#MMPMID26046801
Sharma A
; Gadkari RA
; Ramakanth SV
; Padmanabhan K
; Madhumathi DS
; Devi L
; Appaji L
; Aster JC
; Rangarajan A
; Dighe RR
Sci Rep
2015[Jun]; 5
(?): 11012
PMID26046801
show ga
Higher Notch signaling is known to be associated with hematological and solid
cancers. We developed a potential immunotherapeutic monoclonal antibody (MAb)
specific for the Negative Regulatory Region of Notch1 (NRR). The MAb604.107
exhibited higher affinity for the "Gain-of-function" mutants of Notch1 NRR
associated with T Acute lymphoblastic Leukemia (T-ALL). Modeling of the mutant
NRR with 12 amino-acid insertion demonstrated "opening" resulting in exposure of
the S2-cleavage site leading to activated Notch1 signaling. The MAb, at low
concentrations (1-2??g/ml), inhibited elevated ligand-independent Notch1
signaling of NRR mutants, augmented effect of Thapsigargin, an inhibitor of
mutant Notch1, but had no effect on the wild-type Notch1. The antibody decreased
proliferation of the primary T-ALL cells and depleted leukemia initiating
CD34/CD44 high population. At relatively high concentrations, (10-20??g/ml), the
MAb affected Notch1 signaling in the breast and colon cancer cell lines. The
Notch-high cells sorted from solid-tumor cell lines exhibited characteristics of
cancer stem cells, which were inhibited by the MAb. The antibody also increased
the sensitivity to Doxorubucinirubicin. Further, the MAb impeded the growth of
xenografts from breast and colon cancer cells potentiated regression of the
tumors along with Doxorubucin. Thus, this antibody is potential immunotherapeutic
tool for different cancers.
|Animals
[MESH]
|Antibodies, Monoclonal/*pharmacology/therapeutic use
[MESH]
|Antibody Affinity
[MESH]
|Antineoplastic Agents/*pharmacology/therapeutic use
[MESH]
free
free
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