KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells.
KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells.
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DOI：
10.1158/1078-0432.ccr-16-2152
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发表时间：
2017-05-15
期刊：
影响因子：
--
通讯作者：
Gedrich R
中科院分区：
文献类型：
--
作者：
London CA;Gardner HL;Rippy S;Post G;La Perle K;Crew L;Lopresti-Morrow L;Garton AJ;McMahon G;LaVallee TM;Gedrich R
KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications. Cell proliferation, KIT phosphorylation and mast cell degranulation were evaluated in vitro. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase 1 dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities. KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation in vitro. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (n=5 partial response; n=7 stable disease) was observed regardless of KIT mutation status and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The maximum tolerated dose was established as 10 mg/kg. KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people.
