An anti-TL1A antibody for the treatment of asthma and inflammatory bowel disease

Abstract

TL1A is an attractive therapeutic target for the treatment of mucosal inflammation associated with inflammatory bowel disease (IBD) and asthma. Blockade of the TL1A pathway has been shown to reduce inflammatory responses while leaving baseline immunity intact, and to be beneficial in animal models of colitis and asthma. Given the therapeutic potential of blocking this pathway in IBD and asthma, we developed C03V, a human antibody that binds with high affinity to soluble and membrane-bound TL1A. In an assay measuring apoptosis induced by exogenous TL1A, C03V was 43-fold more potent than the next most potent anti-TL1A antibody analyzed. C03V also potently inhibited endogenous TL1A activity in a primary cell-based assay. This potency was linked to the C03V-binding epitope on TL1A, encompassing the residue R32. This residue is critical for the binding of TL1A to its signaling receptor DR3 but not to its decoy receptor DcR3, and explains why C03V inhibited TL1A-DR3 binding to a much greater extent than TL1A-DcR3 binding. This characteristic may be advantageous to preserve some of the homeostatic functions of DcR3, such as TL1A antagonism. In colitis models, C03V significantly ameliorated microscopic, macroscopic and clinical aspects of disease pathology, and in an asthma model it significantly reduced airways inflammation. Notable in both types of disease model was the reduction in fibrosis observed after C03V treatment. C03V has the potential to address unmet medical needs in asthma and IBD.

TL1A (TNFSF15) genotype affects the long‐term therapeutic outcomes of anti‐TNFα antibodies for Crohn's disease patients

“…In fact, some recent in vivo studies have reported that the anti-TL1A antibody reduces intestinal inflammation and fibrosis in murine colitis models. 28,29,30 This basic evidence indicates that anti-TL1A antibody could be effective for CD, especially for patients homozygous for the TL1A risk haplotype.…”

Risk of Prevalent Asthma among Children Affected by Inflammatory Bowel Disease: A Population-Based Birth Cohort Study

“…IBD and asthma also share a common genetic susceptibility, which includes a polymorphism of gasdermin-B (GSDMB), a protein responsible for regulating differentiation and growth of epithelial cells [35], as well as a polymorphism for the Interleukine 23 receptor gene [36]. Furthermore, these two diseases seem to have a common therapeutic target, TL1A (part of the superfamily of tumor necrosis factor ligands), that, when inhibited by an anti-TL1A antibody, induces a reduction of the mucosal inflammation [37].…”

“…Several biological explanations have been proposed for the association between these two diseases. Among these are possible alterations of the microbiome [32,33], the 'hygiene hypothesis' according to which an increasing prevalence of immune-mediated diseases would be linked to a reduction of antigenic stimuli deriving from pathogens and environmental exposures during early childhood [34], as well as explanations linked to genetic susceptibility [35] and alterations of physiological inflammatory processes [36,37].…”

Intestinal Organoids as a Novel Complementary Model to Dissect Inflammatory Bowel Disease

“…Risankizumab, targeting specifically IL-23, showed promising results in earlier clinical trials [108, 109]. One more recently described cytokine, TL1a, is involved in TNBS colitis and associated fibrosis and has recently been found to be a beneficial target in IBD models, including treatment of fibrosis [110]. PF-06480605, a TL1a targeting agent, is currently under clinical phase II evaluation (NCT02840721).…”