PRA052 has a strong genetic association to IBD
Our second therapeutic candidate, PRA052, is a fully human monoclonal antibody against CD30 ligand (CD30L), a TNF superfamily member. CD30L bears strong genetic and mechanistic links to IBD and represents an attractive target for a precision-enabled approach.
CD30L plays a pleiotropic role in the immune system and uniquely modulates both innate and adaptive immune cells. Not only is CD30L a conventional costimulatory molecule that plays a key role in the stimulation of T cells and B cells by antigen presenting cells, but CD30L has also been shown to conversely stimulate antigen presenting cells known to produce potent pro-inflammatory cytokines, such as IL-1 and IL-6.
We have identified a strong association between CD30L variants and IBD, both at the genetic and functional levels. This association singled out CD30L as a highly relevant costimulatory molecule in the context of IBD. Additionally, it provided some of the SNPs that have been incorporated into a companion diagnostic assay designed to identify patients with an increased chance of response to CD30L antagonism.
The pleiotropic mechanism of action of CD30L is differentiated from other therapeutic agents in IBD. For example, response to anti-CD30L and anti-TNF are unlikely to overlap, as our analysis demonstrated that IBD patients who express a high level of CD30L are less likely to respond to anti-TNF therapy.
PRA052 is slated to begin a Phase 1 study in Q4 of 2022
PRA052 will be the first CDL30 antagonist to enter clinical development, with Ulcerative Colitis as the first planned indication, though we believe the broad applicability of the CD30L pathway makes PRA052 a compelling candidate for a variety of immune-mediated diseases beyond IBD. We are developing a companion diagnostic to prospectively identify Ulcerative Colitis patients who are likely to respond to PRA052.
This program is partnered with Dr. Falk Pharma in Europe, Australia, and New Zealand.
PRA052—a first-in-class opportunity discovered by the Prometheus360™ platform
Through the use of our Prometheus360 platform, we identified associations between several CD30L IBD risk variants and phenotypic observations, including CD30L expression on immune cells and production of the inflammatory cytokines TNFα, IFNγ, and IL-6. We hypothesize that blocking CD30L-CD30 interactions will ameliorate disease in a genetically-identifiable subset of autoimmune disease patients, a concept we will be testing first in patients with Ulcerative Colitis.
CD30-CD30L pathway signaling drives chronic inflammation
The CD30L pathway transcriptional signature is increased in an IBD-impacted colon and in inflamed UC vs non-inflamed control tissue. CD30L antagonism improved colitis in several preclinical models. CD30L signaling is a pleiotropic signal involved in several pro-inflammatory processes including:
- Activation of inflammatory memory T cells by antigen-presenting cells in tissue
- Stimulation of pro-inflammatory, cytokine-producing, tissue myeloid cells
- B cell maturation and proliferation through TFh interactions
The pleiotropic mechanism of action of CD30L is distinct from other therapeutic agents for the treatment of IBD. For example, response to anti-CD30L and anti-TNF are unlikely to overlap as our analysis demonstrated that IBD patients who express a high level of CD30L are less likely to respond to anti-TNF therapy.
CD30L-CD30 expression on Treg is low compared to other costimulatory molecules and as a result, targeting CD30L is expected to be Treg-sparing.
CD30L-CD30 co-stimulation drives chronic inflammation in IBD
IBD is just the beginning
Because CD30L plays a role in several pro-inflammatory signaling pathways, we believe modulating this pathway may have utility in a broad range of immune-mediated diseases beyond IBD.