Anti-HLA-DR antibody treatment tested for canine lymphoma safety

Abstract

Abstract IMMU-114 (also known as hL243) is a humanized anti-HLA-DR monoclonal antibody (mAb) with potent anti-tumor activity against a broad range of human hematopoietic malignancies. As MHC Class II antigens are also expressed on canine lymphocytes, IMMU-114 has previously been found to recognize and kill malignant lymphocytes collected from dogs with spontaneous B cell lymphoma. Canine lymphoma is a highly relevant animal model of B-cell non-Hodgkin's lymphoma (NHL) in humans with many advantages over rodent models. In addition, clinical trials in pet dogs can be designed to address therapeutic endpoints relevant to phase II/III studies in both dogs and humans. This study is being undertaken to determine the safety, pharmacodynamic and pharmacokinetic profiles of IMMU-114 in dogs with heavily pre-treated B cell lymphoma (NHL). Our hypothesis is that the mAb can safely be administered to tumor-bearing dogs and that it will be preferentially cytotoxic to B lymphocytes. Our overall objectives are to characterize the toxicity and biologic profile of IMMU-114 to advance the therapy of canine lymphoma and to better inform human clinical trials using anti-HLA-DR mAbs. Thirteen pet dogs with B cell lymphoma demonstrating binding to IMMU-114 have been enrolled in an on-going phase I clinical trial at the Flint Animal Cancer Center at Colorado State University. Enrollment follows a standard 3 x 3 dose escalation to identify the maximally tolerated dose (MTD) of the mAb, starting at a dose of 3 mg/kg, and escalating thus far to 6, 12, and 24 mg/kg. Data collection includes pre and post-infusion peripheral blood mononuclear cells (PBMCs), serum, serial lymph node measurements, complete blood counts and serum chemistry profiles. Preliminary pharmacodynamic evaluation shows a significant and transient dose-dependent decrease in the percentage and absolute number of B lymphocytes in the blood of treated dogs 24 hours post infusion. This corresponds to a transient increase in the relative percentage of T lymphocytes. Neutropenia and other bone marrow toxicities have not been observed. Infusion related side effects appear common but have been mild to moderate in nature with 10/13 patients experiencing grade 1 or grade 2 allergic reactions (fever, urticaria, and hypersalivation) and 2/13 with grade 1 nausea. No dose limiting toxicities have been observed; therefore the MTD has not yet been reached. Thus far 2/13 dogs (15%) have had prolonged disease stabilization and received multiple weekly infusions of 12 mg/kg while 11/13 dogs have had progressive disease (lymph node enlargement) within one week post therapy. Pharmacokinetic data obtained at the end of infusion, 2, 24 hours and 1 and 2 weeks post infusion showed minimally detectable levels at doses of 3 and 6 mg/kg. At 12 mg/kg, 2 animals had evidence of persistent antibody levels in serum for 24 hours, followed by return to pre-treatment levels within 6 days. Two dogs currently treated at 24 mg/kg maintained hL243 levels in their blood over 1 day, with residual antibody still found in the blood 6 days later Four of the 13 dogs developed anti-hL243 responses 2 to 4 weeks after treatment initiation. These findings provide a rationale for larger clinical studies to investigate the efficacy of anti-HLA-DR mAbs for both veterinary and human applications. Citation Format: Barbara J. Biller, Rodney Page, Robert Sharkey, David M. Goldenberg. Phase I evaluation of anti-human leukocyte antigen-DR monoclonal antibody therapy in spontaneous canine lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A07.