Targeting cytokines and immune checkpoints in atherosclerosis with monoclonal antibodies

Abstract

Over the past fifteen years, treatments using monoclonal antibodies specifically targeting cytokines have been developed to treat chronic inflammatory diseases, including rheumatoid arthritis or psoriasis, both associated with increased cardiovascular risk. The cardiovascular impact of these therapies allows us to validate the clinical relevance of the knowledge acquired from experimental studies about the role of cytokines in atherosclerosis. Several clinical studies have confirmed the protective effects of anti-TNFα and anti-IL-6R monoclonal antibodies against athero-thrombotic cardiovascular risk in patients with chronic inflammatory diseases. Yet, caution is needed since anti-TNFα treatment can aggravate chronic heart failure. More recently, the CANTOS study showed for the first time that an anti-inflammatory treatment using anti-IL-1β monoclonal antibody in coronary artery disease patients significantly reduced cardiovascular events. The effects of IL-23/IL-17 axis blockade on cardiovascular risk in patients with psoriasis or arthritis remain controversial. Several monoclonal antibodies targeting costimulatory molecules have also been developed, a direct way to confirm their involvement in atherothrombotic cardiovascular diseases. Blocking the CD28 − CD80/86 axis with Abatacept has been shown to reduce cardiovascular risk. In contrast, the treatment of cancer patients with antibodies blocking immune checkpoint inhibitory receptors, such as CTLA-4, PD1, or PDL1, could worsen the risk of atherothrombotic events. In the future, cardiologists will be increasingly solicited to assess the cardiovascular risk of patients suffering from chronic inflammatory diseases or cancer and participate in choosing the most appropriate treatment. At the same time, immunomodulatory approaches directly targeting cardiovascular diseases will be developed as a complement to the usual treatment strategies.

CD40L modulates CD4+ T‐cell activation through receptor for activated C kinase 1

“…Inhibition of CD40L has shown beneficial effects in many experimental models of auto-immune and chronic inflammatory diseases. Blocking CD40L/CD40 signaling has been shown to substantially reduce atherosclerotic burden, and improve inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis in clinical trials and experimental mouse models [25,[46][47][48][49][50].…”

Relationship of Soluble Lectin‐Like Low‐Density Lipoprotein Receptor‐1 (sLOX‐1) With Inflammation and Coronary Plaque Progression in Psoriasis

“… 36 , 37 Over the past decade, monoclonal antibodies, against interleukin‐1β and interleukin‐17A, have been used to target pathogenesis of chronic inflammatory diseases, like psoriasis. 38 , 39 , 40 The CANTOS (Canakinumab Anti‐Inflammatory Thrombosis Outcomes Study) demonstrated evidence of targeting chronic inflammation to improve clinical outcomes, such as coronary plaque levels, in patients with atherosclerosis. 38 It has been demonstrated before that biologic therapy in severe psoriasis patients was associated with favorable modulation on coronary plaque phenotype measured by CCTA.…”

“… 38 , 39 , 40 The CANTOS (Canakinumab Anti‐Inflammatory Thrombosis Outcomes Study) demonstrated evidence of targeting chronic inflammation to improve clinical outcomes, such as coronary plaque levels, in patients with atherosclerosis. 38 It has been demonstrated before that biologic therapy in severe psoriasis patients was associated with favorable modulation on coronary plaque phenotype measured by CCTA. 4 With the current analyses, we sought to further understand the effect that elevated sLOX‐1 levels might have on coronary plaque progression in patients under specific psoriatic treatment.…”

Atherosclerosis With Immune Checkpoint Inhibitor Therapy

“…While the molecular pathways of ICI-associated atherosclerosis beyond PD-1, PD-L1, and CTLA-4 are incompletely understood, approaches targeting novel co-stimulatory and co-inhibitory immune checkpoints, are currently under investigation ( Table 2 ). 58 , 59 , 60 …”