 |
PDBsum entry 4k9e
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Immune system
|
PDB id
|
|
|
|
4k9e
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
221 a.a.
|
|
|
|
|
|
|
|
|
|
|
220 a.a.
|
|
|
|
|
|
|
|
|
|
|
193 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for kit receptor tyrosine kinase inhibition by antibodies targeting the d4 membrane-Proximal region.
|
|
|
Authors
|
|
A.V.Reshetnyak,
B.Nelson,
X.Shi,
T.J.Boggon,
A.Pavlenco,
E.M.Mandel-Bausch,
F.Tome,
Y.Suzuki,
S.S.Sidhu,
I.Lax,
J.Schlessinger.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2013,
110,
17832-17837.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Somatic oncogenic mutations in the receptor tyrosine kinase KIT function as
major drivers of gastrointestinal stromal tumors and a subset of acute myeloid
leukemia, melanoma, and other cancers. Although treatment of these cancers with
tyrosine kinase inhibitors shows dramatic responses and durable disease control,
drug resistance followed by clinical progression of disease eventually occurs in
virtually all patients. In this report, we describe inhibitory KIT antibodies
that bind to the membrane-proximal Ig-like D4 of KIT with significant overlap
with an epitope in D4 that mediates homotypic interactions essential for KIT
activation. Crystal structures of the anti-KIT antibody in complex with KIT D4
and D5 allowed design of affinity-matured libraries that were used to isolate
variants with increased affinity and efficacy. Isolated antibodies showed KIT
inhibition together with suppression of cell proliferation driven by
ligand-stimulated WT or constitutively activated oncogenic KIT mutant. These
antibodies represent a unique therapeutic approach and a step toward the
development of "naked" or toxin-conjugated KIT antibodies for the
treatment of KIT-driven cancers.
|
|
|
|
|
|
|
