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. 2017 May 15;23(10):2565-2574.
doi: 10.1158/1078-0432.CCR-16-2152. Epub 2016 Nov 4.

KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity Against Both Normal and Malignant Canine Mast Cells

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Free PMC article

KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity Against Both Normal and Malignant Canine Mast Cells

Cheryl A London et al. Clin Cancer Res. .
Free PMC article

Abstract

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 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 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 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 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.

Conflict of interest statement

Conflicts of Interest: LC, LL-M, AG, GM, TL and RG are employees of Kolltan

Figures

Figure 1
Figure 1. KTN0158 potently inhibits KIT activity and function in M-07e cells and primary human mast cells in vitro
(A) KTN0158 inhibited KIT activation and downstream signaling in M-07e cells. Dose-dependent inhibition of KIT, ERK1/2 and AKT activation were observed flowing KTN0158 treatment. KTN0062C is an isotype control antibody. (B) KTN0158 was a more potent inhibitor of SCF-dependent proliferation in M-07e cells compared to imatinib and nilotinib. Dashed lines represent proliferation observed in controls grown in the presence (+SCF) or absence (-SCF) of SCF. Representative data are shown for six independent experiments. Analyses were performed in duplicate (KTN0158) or triplicate (all others) and data are plotted as means ± standard error of the mean (SEM). (C) KTN0158 was a more potent inhibitor of SCF-induced KIT phosphorylation in primary human mast cells in vitro than imatinib. Representative data are shown for four independent mast cell preparations and runs. Analyses were performed in duplicate and data are plotted as means ± SEM. (D) KTN0158 was a potent inhibitor of SCF enhancement of mast cell degranulation. In both (C) and (D), the isotype control is KTN0062C and analyses were performed in duplicate with data plotted as means ± SEM.
Figure 2
Figure 2. KTN0158 is a potent inhibitor of canine KIT and modulates canine mast cells in vivo
(A) KTN0158 inhibited SCF-induced KIT activation in CHO cells stably expressing wild-type canine KIT. (B) KTN0158 decreased the number of mast cells in the skin of healthy dogs within 7 days following drug administration. Data are plotted as means ± standard error of the mean. This effect was dose-dependent, with 30 mg/kg demonstrating continued suppression of mast cells at day 28 post treatment.
Figure 3
Figure 3. KTN0158 treatment results in objective responses in canine MCT with and without exon 11 mutations
(A) Best responses after KTN0158 administration are shown and demonstrate that all dogs experienced clinical benefit. Dose and cohort are indicated. Exon 11 ITD denotes dogs with exon 11 mutations. (B) Tumor measurements demonstrating a partial response to KTN0158 treatment in one dog that occurred between Day 0 (left panel) and Day 14 (right panel). This dog had failed multiple treatment modalities prior to receiving KTN0158. (C) Target modulation was observed in MCTs 24 hours after KTN0158 administration. Decreases in KIT phosphorylation were noted in most tumors with evaluable signals prior to dosing (n = 8), including evaluable tumors with exon 11 mutations.

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