Abstract
BACKGROUND: Chronic inflammatory conditions are among the leading causes of disability and mortality. Although therapies have been significantly improved with the introduction of target-specific biologics, many chronic inflammatory conditions can be only moderately controlled by inhibition of individual cytokines. OBJECTIVE: We sought to compare individual versus simultaneous blockade of TNF-α and OX40L in controlling inflammation. METHODS: Analysis was conducted of the murine xenograft graft-versus-host disease model, a novel cynomolgus monkey model of simultaneous T cell-dependent antibody response (TDAR) and delayed-type hypersensitivity (DTH) skin reaction, and samples of patients with hidradenitis suppurativa (HS). RESULTS: Compared with individual inhibition, combined targeting of TNF-α and OX40L using mAbs more potently suppressed TDAR and DTH in cynomolgus monkey. We therefore created SAR442970, a bispecific pentavalent Nanobody containing 2 domains each binding to OX40L and TNF-α and 1 domain binding serum albumin to extend half-life. In xenograft graft-versus-host disease, disease control by SAR442970 was superior compared with treatment with monospecific anti-TNF-α or anti-OX40L Nanobodies. In cynomolgus monkey, SAR442970 potently suppressed TDAR and DTH. The transcriptional signature of inflamed monkey skin showed similarities to that of lesional skin of patients with atopic dermatitis and, even more so, HS and was inhibited by SAR442970 treatment. Increased numbers of cells expressing OX40 were observed in HS lesions, and bioinformatics analyses of single-cell and bulk RNA sequencing data identified cells expressing OX40 as T cells with a highly mobile phenotype. CONCLUSION: OX40-OX40L interaction is a key pathogenetic feature in HS, and patients with HS might benefit from combined TNF-α/OX40L blockade by SAR442970, which is currently investigated in a clinical phase 2 trial.