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Published on: September 28, 2018
Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region
Andrey V Reshetnyak1, Bryce Nelson, Xiarong Shi
1Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
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.
Insights
Researchers developed novel KIT antibodies that inhibit cancer cell growth. These antibodies target KIT mutations driving cancers like GIST and AML, offering a new therapeutic strategy against drug resistance.
Area of Science:
- Oncology
- Immunology
- Structural Biology
Background:
- Somatic mutations in receptor tyrosine kinase KIT drive gastrointestinal stromal tumors (GIST) and other cancers.
- Tyrosine kinase inhibitors (TKIs) are effective but often lead to drug resistance and disease progression.
Purpose of the Study:
- To develop novel inhibitory KIT antibodies targeting KIT activation.
- To overcome TKI resistance in KIT-driven cancers.
Main Methods:
- Designed and isolated affinity-matured KIT antibodies targeting the membrane-proximal Ig-like D4 domain.
- Utilized crystal structures of KIT-antibody complexes for antibody engineering.
- Assessed antibody efficacy in inhibiting KIT and suppressing cancer cell proliferation.
Main Results:
- Developed inhibitory KIT antibodies binding to a critical KIT activation epitope.
- Demonstrated antibody-mediated KIT inhibition and suppression of proliferation in KIT-driven cancer cells.
- Engineered antibodies with increased affinity and efficacy through affinity maturation.
Conclusions:
- Novel KIT antibodies offer a promising therapeutic strategy for KIT-driven cancers.
- These antibodies can overcome resistance mechanisms associated with current TKIs.
- Development of naked or toxin-conjugated KIT antibodies represents a new frontier in cancer therapy.
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