Abstract
Canine B-cell lymphoma (CBL) is an incurable, spontaneous lymphoid malignancy constituting an accurate animal model for testing novel therapeutic strategies in human medicine. Resources of available species-specific therapeutic monoclonal antibodies (mAbs) targeting CBL are scarce. The aim of the present study was to evaluate the therapeutic potential of mAb B5, specific for the dog leukocyte antigen DR (DLA-DR) and its antibody-drug conjugate with methotrexate (B5-MTX). B5 induced caspase-dependent apoptosis of DLA-DR-expressing canine B cell lymphoma/CLBL1 and CLB70 leukemia lines, but not the GL-1 line not expressing DLA-DR. The cytotoxicity of B5-MTX to sensitive cells was further potentiated by a payload of MTX, but without any substantial off-target effects. The infusion of B5 and B5-MTX in a murine model of disseminated, advanced canine lymphoma, mediated >80% and >90% improvement in survival, respectively, and was well tolerated by the animals. Interestingly, the concentrations of soluble DLA-DR (sDLA-DR) antigens present in the blood serum of tumor-bearing mice were found proportional to the tumor burden. On this basis, sDLA-DR levels were evaluated as a potential biomarker using samples from canine lymphoma patients. In summary, the action of B5 and B5-MTX holds promise for further development as an alternative/complementary option for the diagnosis and treatment of canine lymphoma.
Highlights
Canine B cell lymphoma (CBL) is a spontaneous malignancy bearing numerous molecular, histopathological and clinical similarities to human non-Hodgkin lymphoma (NHL) [1]
Versus B5 ADC with methotrexate (B5-MTX) revealed a delay in retention times, which was due to the versus B5-MTX revealed a delay in retention times, which was due to the high average drug to antibody substitution ratio (DAR), estimated at 42.6 (Figure 1A)
We tested a novel MTX-based antibody-drug conjugate (ADC) directed against canine lymphoma/leukemia cells
Summary
Canine B cell lymphoma (CBL) is a spontaneous malignancy bearing numerous molecular, histopathological and clinical similarities to human non-Hodgkin lymphoma (NHL) [1]. For this reason, dogs are considered an important animal model for pre-clinical testing of new therapies for human lymphoma [2,3]. CBL is the most frequent hematological malignancy with various histopathological presentations and accounts for over 60% of all diagnosed lymphoma cases in dogs [4]. 16,000 to 80,000 dogs owned in the United States alone suffer from hematological malignancies annually [5,6]. Relapses of the disease are usually observed within 10–14 months post-treatment, with less than 25% of dogs surviving two years [2]
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