Humanized anti-BAMBI monoclonal antibody as a novel therapeutic strategy for psoriatic arthritis

Abstract

Psoriasis (PsO) is a chronic autoimmune skin disease that affects 2% of the global population, with 30% of patients progressing to psoriatic arthritis (PsA). Both conditions are primarily mediated by CD4 + T cells, whose differentiation into distinct subpopulations depends on the surrounding cytokine composition. In this regard, TGFβ plays a dual role, driving the differentiation to both pro-inflammatory Th17 cells, and protective Tregs. During psoriasis and PsA development, there is an increase in the production of Th17 cells, while the protective axis does not work efficiently. Thus, current therapies mainly target pro-inflammatory mediators, blocking cytokines such as TNFα or the IL-17 axis. However, in about 35–40% of PsA patients these treatments do not reach the minimum level of efficacy, and the later appearance of drug resistances is frequent. We have developed hB101.37, humanized monoclonal antibody (mAb) that inhibits BAMBI (BMP and Activin Membrane-Bound Inhibitor). hB101.37 mAb therapeutic effect was assessed using pre-clinical murine models of psoriasis (Imiquimod and IL-21-induced PsO) and psoriatic arthritis (mannan-induced PsA). Murine samples were used to evaluate toxicity by histological and immunofluorescence analyses, ELISA assay and qPCR. Additionally, transthoracic echocardiography was performed following chronic administration of hB101.37 mAb to analyze cardiac disfunction. In vitro and in vivo effects of hB101.37 mAb on immune cell subpopulations were assessed in murine and human cells CD4 + T cells by staining and flow cytometry analyses. Molecular signaling evaluation was tested by activation of Smad2/3 pathway using western blot. Our findings confirmed the therapeutic efficacy of hB101.37 mAb in PsO and PsA, validating it as a first in class antibody with a novel mechanism of action that reduces pro-inflammatory Th17 cells while promoting differentiation towards Treg population. Anti-BAMBI therapy shown potential greater clinical efficacy in psoriasis compared to alternative treatments used at the clinic such as anti-IL-17A mAb. Furthermore, our results from the pre-clinical phase have confirmed the safety profile of this therapeutic antibody. Our present findings point to BAMBI inhibition as an innovative and promising approach for the treatment of psoriasis and PsA.