Abstract 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-α signaling directly on tumor-supporting CAFs drives reprogramming, countering the TGF-β signal on which the phenotype depends. IFN-α 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-α therapy has been limited by significant dose-limiting toxicities. We have generated a conditionally active cLRRC15-IFNα therapeutic that targets IFN-α 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-α 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-IFNα exerts anti-tumor activity both by direct cis-signaling of IFN-α on CAFs and by trans-signaling to adjacent immune cells. In vitro, reporter cell and receptor binding assays demonstrate that cLRRC15-IFNα has 100-fold preferential IFN-α activity in the presence of LRRC15. In primary cells, cLRRC15-IFNα preferentially induces IFN-α signaling in LRRC15-expressing activated human fibroblasts. cLRRC15-IFNα inhibits tumor growth in mouse syngeneic tumor models, avoids clinical signs of IFN-α-mediated toxicity, and demonstrates robust combinatorial activity with anti-PD-1. In the TME, cLRRC15-IFNα drives the activation of CD8+ T cells. Collectively, these results demonstrate the potential of the DBA platform and support the clinical development of cLRRC15-IFNα. Citation Format: Justin Killebrew, Linda Liang, Shannon Okada, Aelish Guinn, Alton Etheridge, Brett Robison, David Colby, David Jurchen, Jacqueline Pham, Jamie Nguyen, John Skonier, Kendyl Daniels, Kerri Thomas, Laura Carlucci, Lynn Amon, Megan Sprague, Meri Galindo, Remington Lance, Sam Wrenn, Sandra Notonier, Shannon Fallen, Shea McClain, Wendy Curtis, Zane Kraft, John Mulligan, Diane Hollenbaugh, . Safety and activity of cLRRC15-IFNa, a conditionally active biologic targeting IFNa specifically to LRRC15+ CAFs abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2892.
Killebrew et al. (Fri,) studied this question.