OX40L Inhibition Suppresses KLH‐driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof‐of‐Pharmacology for KY1005

Abstract

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti‐OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty‐four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure‐response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax) ~ 4 hours, geometric mean terminal half‐life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) −13.4 arbitrary unit (AU), 95% confidence interval (CI) −23.0 AU to −3.8 AU) and erythema quantified as average redness (ED −0.23 AU, 95% CI −0.35 AU to −0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure‐response analysis displayed a statistically significant treatment effect on anti‐KLH antibody titers (IgG maximum effect (Emax) −0.58 AU, 95% CI −1.10 AU to −0.06 AU) and skin response (erythema Emax −0.20 AU, 95% CI −0.29 AU to −0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune‐mediated disorders.

Characterization of KLH-driven immune responses in clinical studies: A systematic review

“…Because of the lower immunogenicity, subunit KLH is often used concurrently with an adjuvant, such as aluminum hydroxide (Edelman, 1980). Out of the 9 studies that used an adjuvant together with subunit KLH, participants were immunized with subunit KLH adsorbed to aluminum hydroxide in 7 studies (Boulton et al, 2012;Poirier et al, 2016;Saghari et al, 2020;Saghari et al, 2022;Smith et al, 2004a;Smith et al, 2004b;Spazierer et al, 2009). Valdez H, et al, 2000(Valdez et al, 2000 TIA*** Proliferation 10x (5-20x)** Kantele A, et al, 1999(Kantele et al, 1999 IgM increased (variability unclear) de Fijter JW, et al, 1996(Fijter et al, 1996 Snyder BK, et al, 1993(Snyder et al, 1993 TIA*** Proliferation 3.8x (-1.7-9.5x) Falconer AE, et al, 1992(Falconer et al, 1992 Immunizations with doses of 1 μg-5,000 μg have been reported, with 100 μg being the most frequently used dose (Figure 2).…”

“…Valdez H, et al, 2000(Valdez et al, 2000 TIA*** Proliferation 10x (5-20x)** Kantele A, et al, 1999(Kantele et al, 1999 IgM increased (variability unclear) de Fijter JW, et al, 1996(Fijter et al, 1996 Snyder BK, et al, 1993(Snyder et al, 1993 TIA*** Proliferation 3.8x (-1.7-9.5x) Falconer AE, et al, 1992(Falconer et al, 1992 Immunizations with doses of 1 μg-5,000 μg have been reported, with 100 μg being the most frequently used dose (Figure 2). (Birdsall and Rossen, 1983;Boulton et al, 2012;Husby et al, 1994;Kantele et al, 1999;Kantele et al, 2011;Kraus et al, 2004;Lange et al, 2003;Moldoveanu et al, 2004;Ochs et al, 1988;Otterhaug et al, 2021;Paty et al, 1975;Smith et al, 2004a;Smith et al, 2004b;Spazierer et al, 2009;Poirier et al, 2016;Saghari et al, 2020;Saghari et al, 2022;Snyder et al, 1993;Waldo et al, 1994) Higher KLH immunization doses have been used in earlier studies and in studies using subunit KLH alone compared to studies using HMW-KLH or subunit KLH with an adjuvant (Table 1). Notably, Belson et al used a high KLH immunization dose of 5,000 μg causing a participant withdrawal rate of approximately 38% due to large local reactions following a single subcutaneous administration (Belson et al, 2016).…”

“…Intranasal KLH inhalation has also been reported, however, sufficient penetration of KLH through the mucosal tissue likely requires higher (cumulative) KLH doses in order to exert measurable systemic immune responses (Salvaggio et al, 1969;Waldo et al, 1994;Diaz-Sanchez et al, 1999). Intradermal KLH administration is the preferential administration route when analyzing the skin response after KLH rechallenge (Salvaggio et al, 1969;Curtis and Hersh, 1972;Brunner et al, 1973;Palestine et al, 1985;Ashorn et al, 1986;Husby et al, 1994;Waldo et al, 1994;Valdez et al, 2000;Rentenaar et al, 2002;Lange et al, 2003;Smith et al, 2004a;Boelens et al, 2004;Smith et al, 2004b;Moldoveanu et al, 2004;Spazierer et al, 2009;Boulton et al, 2012;Milgrom et al, 2012;Hostmann et al, 2015;Belson et al, 2016;Saghari et al, 2020;Saghari et al, 2022). The arm is most often used for KLH Waldo FB, et al, 1994(Waldo et al, 1994) Diameter Induration 11.9 mm (0-23 mm) Husby S, et al, 1995(Husby et al, 1994) Diameter Induration 11.9 mm (0-23 mm) Ashorn RG, et al, 1986(Ashorn et al, 1986) Diameter Induration 17.5 mm (10-25 mm) Palestine AG, et al, 1985(Palestine et al, 1985 Diameter Induration 15.4 mm (8-20 mm)** Brunner CM, et al, 1973(Brunner et al, 1973 Diameter Induration 15 mm (single subject) Curtis JE, et al, 1972 (Curtis andHersh, 1972) Diameter Induration 8.7 mm (0-18 mm) Salvaggio J, et al,...…”

“…Analysis methods varied from enzyme-linked immunosorbent assay (ELISA) to hemagglutination assay (HA), radioimmunoassay (RIA), and cytometric bead array (CBA) (Table 2). The majority of the studies had used ELISA to quantify KLHspecific antibodies (Volkman et al, 1981;Palestine et al, 1985;Bird et al, 1990;Ward et al, 1990;Falconer et al, 1992;Husby et al, 1994;Waldo et al, 1994;Fijter et al, 1996;Kondratenko et al, 1997;Schuyler et al, 1997;Rentenaar et al, 2002;Lange et al, 2003;Smith et al, 2004a;Boelens et al, 2004;Smith et al, 2004b;Kraus et al, 2004;Moldoveanu et al, 2004;Miller et al, 2005;Spazierer et al, 2009;Kapp et al, 2010;Boulton et al, 2012;Milgrom et al, 2012;Hostmann et al, 2015;Poirier et al, 2016;Giesecke et al, 2018;Saghari et al, 2020;Otterhaug et al, 2021;Yang et al, 2021;Saghari et al, 2022).…”

“…The antigen-specific cell-mediated immunity can be studied locally by challenging the skin with intradermal KLH, after an initial immunization. This T cell-driven inflammatory response usually takes more than 12 h to develop, and the maximal response time usually occurs between 24 and 72 h. The effects induced by the intradermal KLH rechallenge are likely to be driven by a mixed reaction of innate immune responses (Spazierer et al, 2009), T cell-driven delayed-type hypersensitivity (DTH) (Spazierer et al, 2009;Belson et al, 2016;Saghari et al, 2020;Saghari et al, 2022), and partially Th2 cell-type late-phase skin response effects (Spazierer et al, 2009).…”