Year: 2026
Type: conference-abstract
Abstract: Background Despite great advances in cancer immunotherapy, e.g., with immune checkpoint inhibitors, most patients fail to respond, or develop resistance. Soluble CD80-Fc fusion proteins with either the IgV-like (IgV) domain or the full extracellular domain (ECD) of CD80 may facilitate T cell activation not only by co-stimulating CD28 but also by blocking the inhibitory activities of CTLA-4 and PD-L1. We are developing BP-80, a CD80-Fc fusion protein with the full wild-type CD80 ECD, thereby differing from davoceticept (ALPN-202), a potency-enhanced CD80 IgV-Fc fusion protein associated with severe cardiac toxicity. The Fc portion of BP-80 incorporates the L234A/L235A ‘LALA’ mutation to reduce ADCC, ADCP, and CDC.Methods We have characterized BP-80 in CD80/CD28 co-stimulation and CTLA-4 cell inhibition assays, both requiring the co-culturing of target and engineered Jurkat reporter cells with IL-2 promoter-driven luciferase. We also addressed BP-80’s toxicity and pharmacokinetics in cynomolgus monkeys, at doses of 0 (vehicle), 0.5, 5, and 50 mg/kg.Results BP-80 dose-dependently enhanced the luciferase signal in the presence but not absence of target cells (CHO-K1 cells engineered to express CD32b (FcgRIIb)), consistent with a mechanism of action in which BP-80:CD28 co-stimulation was dependent on Fc receptor (FcR) engagement ( figure 1). Similarly, in a CTLA-4 blockade reporter assay using Raji cells expressing CD80/CD86, BP-80 elicited a dose-dependent reporter response comparable to that of an anti-CTLA-4 antibody (Yervoy biosimilar), but only in the presence of anti-Fc antibody. BP-80 therefore functionally reversed CTLA-4 engagement by membrane CD80/CD86 in an Fc-crosslinking-dependent manner, consistent with avidity-enhanced competition for CTLA-4 binding (figure 2). In monkeys, the no observed effect level (NOEL) was 50 mg/kg/day and the half-life of BP-80 ranged from 8.62 to 22.9 hours.Conclusions BP-80 antagonized the T cell-inhibitory activities of CTLA-4 and reactivated the CD28 pathway, and did not show toxicity limiting further human development.Abstract 404 Figure 1 BP-80 mediated CD28 co-stimulation assay. (A) Schematic; (B) CHO-K1/CD32b cells were co-cultured with Jurkat-IL2-luc cells (IL-2 cells) in the presence of increasing concentrations of BP-80 Drug Substance (NF5E DS), anti-CD28 antibody or human IgG (control). N = 3Abstract 404 Figure 2 CTLA-4 Assay. (A) Schematic; (B) Raji APC cells were co-cultured with Jurkat CTLA-4 effector cells in the presence of increasing concentrations of anti-CTLA-4 antibody (Ab) (Yervoy biosimilar), BP-80 (NF5E) ± anti-Fc Ab, or commercially available CD80-Fc ± anti-Fc Ab
Institutions: University of Utah, Huntsman Cancer Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225185577