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

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 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. 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 maximum tolerated dose was established as 10 mg/kg. Conclusion 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.

Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View

“…For the reason that the majority of GISTs express KIT which was retained in refractory GISTs after small molecule treatment, anti-KIT monoclonal antibodies were investigated in preclinical setting and might move forward to clinical trials in the future [27,28].…”

Introducing fluorescence guided surgery into orthopedic oncology: A systematic review of candidate protein targets for Ewing sarcoma

“…They provided proof of concept and confirmed that KIT could be accurately labeled in GISTs for detection of primary tumors, as well as for detection of small metastatic deposits that might be missed at the time of surgical resection. The recently developed humanized monoclonal antibody KTN0158 is being evaluated in dogs for therapeutic purposes and might eventually have potential for imaging …”

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

“…A single injection of anti-c-kit antibodies shortly after birth resulted in a prolonged suppression of melanoma, a greatly increased tumor-free period, and none of the animals injected with anti-c-kit antibodies died from cancer for 12 months after birth [ 99 ]. Another group of researchers developed humanized anti-c-kit monoclonal antibodies, KTN0158, that specifically interact with both mutant and wild-type c-kit and exhibit biological activity in normal and malignant mast cells [ 100 ]. In 2015, Kolltan Pharmaceuticals launched a phase I clinical trial of anti-c-kit monoclonal antibodies, KTN0158, as a monotherapeutic agent for the treatment of patients with gastrointestinal stromal tumors and other c-kit-positive tumors ( NCT02642016 ).…”