Safety and activity of cLRRC15-IFNa, a conditionally active biologic targeting IFNa specifically to LRRC15+ CAFs

While cancer-associated fibroblasts (CAFs) have emerged as a key cell type capable of influencing malignant cell growth, this axis of cancer biology has not yet been exploited for therapeutic benefit. CAFs enable tumor growth through multiple mechanisms including deposition of extracellular matrix, production of soluble factors, and inhibition of the immune response. Recent advancements have revealed how distinct CAF populations correlate with patient prognosis and response to therapies across many solid tumor types. Amongst these CAF subsets, LRRC15 expression has been shown to identify a myofibroblast population with a central functional role in supporting tumor cell growth and inhibiting anti-tumor immune responses. Approaches to reprogram or reduce this LRRC15+ population of CAFs may provide therapeutic benefit in multiple solid tumor indications. IFN-alpha signaling directly on tumor-supporting CAFs drives reprogramming, countering the TGF-beta signal on which the phenotype depends. IFN-alpha also effectively promotes both innate and adaptive immune responses, including dendritic cell maturation, repolarization of suppressive myeloid cells, and CD8+ T cell activation. However, the use of systemic IFN-alpha therapy has been limited by significant dose-limiting toxicities. We have generated a conditionally active cLRRC15-IFNalpha therapeutic that targets IFN-alpha activity to LRRC15+ cells while remaining largely inactive on other cells. Our approach uses a novel dual-binding antibody (DBA) mechanism that takes advantage of the ability of an antibody to bind specifically and competitively to two distinct antigens. With this technology, IFN-alpha is bound and inactive in circulation and only becomes active when the therapeutic binds to LRRC15. Once localized to the surface of an LRRC15+ CAF, cLRRC15-IFNalpha exerts anti-tumor activity both by direct cis-signaling of IFN-alpha on CAFs and by trans-signaling to adjacent immune cells. In vitro, reporter cell and receptor binding assays demonstrate that cLRRC15-IFNalpha has >100-fold preferential IFN-alpha activity in the presence of LRRC15. In primary cells, cLRRC15-IFNalpha preferentially induces IFN-alpha signaling in LRRC15-expressing activated human fibroblasts. cLRRC15-IFNalpha inhibits tumor growth in mouse syngeneic tumor models, avoids clinical signs of IFN-alpha-mediated toxicity, and demonstrates robust combinatorial activity with anti-PD-1. In the TME, cLRRC15-IFNalpha drives the activation of CD8+ T cells. Collectively, these results demonstrate the potential of the DBA platform and support the clinical development of cLRRC15-IFNalpha.