KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells.
Purpose: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.Experimental Design:Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluatedin vitroKTN0158 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 I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities.Results:KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulationin vitroIn 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 ofKITmutation 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 MTD was established as 10 mg/kg.Conclusions: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.Clin Cancer Res; 23(10); 2565-74. ©2016 AACR.
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio. london.20@osu.edu.|Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, Ohio.
Cheryl A
CA
London
Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, Ohio.
Heather L
HL
Gardner
Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, Ohio.
Sarah
S
Rippy
The Veterinary Cancer Center, Norwalk, Connecticut.
Gerald
G
Post
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
Krista
K
La Perle
Kolltan Pharmaceuticals, Inc., New Haven, Connecticut.
Linda
L
Crew
Kolltan Pharmaceuticals, Inc., New Haven, Connecticut.
Lori
L
Lopresti-Morrow
Kolltan Pharmaceuticals, Inc., New Haven, Connecticut.
Andrew J
AJ
Garton
Kolltan Pharmaceuticals, Inc., New Haven, Connecticut.
Gerald
G
McMahon
Kolltan Pharmaceuticals, Inc., New Haven, Connecticut.
Theresa M
TM
LaVallee
Kolltan Pharmaceuticals, Inc., New Haven, Connecticut.
Richard
R
Gedrich
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004283:Dog Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D004285:Dogs; D005260:Female; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D009154:Mutation; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*
D000911:Antibodies, Monoclonal; D019009:Proto-Oncogene Proteins c-kit