First‐in‐human study of the safety,tolerability, pharmacokinetics,and pharmacodynamics of ALPN‐101, a dual CD28/ICOS antagonist,in healthy adult subjects

ALPN‐101 (ICOSL vIgD‐Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD) designed to inhibit the cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) pathways simultaneously. A first‐in‐human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy adult subjects. ALPN‐101 was generally well‐tolerated with no evidence of cytokine release, clinically significant immunogenicity, or severe adverse events following single subcutaneous (SC) doses up to 3 mg/kg or single intravenous (IV) doses up to 10 mg/kg or up to 4 weekly IV doses of up to 1 mg/kg. ALPN‐101 exhibited a dose‐dependent increase in exposure with an estimated terminal half‐life of 4.3–8.6 days and SC bioavailability of 60.6% at 3 mg/kg. Minimal to modest accumulation in exposure was observed with repeated IV dosing. ALPN‐101 resulted in a dose‐dependent increase in maximum target saturation and duration of high‐level target saturation. Consistent with its mechanism of action, ALPN‐101 inhibited cytokine production in whole blood stimulated by Staphylococcus aureus enterotoxin B ex vivo, as well as antibody responses to keyhole limpet hemocyanin immunization, reflecting immunomodulatory effects upon T cell and T‐dependent B cell responses, respectively. In conclusion, ALPN‐101 was well‐tolerated in healthy subjects with dose‐dependent PK and PD consistent with the known biology of the CD28 and ICOS costimulatory pathways. Further clinical development of ALPN‐101 in inflammatory and/or autoimmune diseases is therefore warranted.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

ALPN‐101 is an Fc fusion protein of a human inducible T cell costimulatory ligand variant immunoglobulin domain designed to block the cluster of differentiation 28 CD28) and inducible T cell costimulator (ICOS) simultaneously, thereby inhibiting two key costimulatory pathways in T lymphocytes. Although inhibitors of each pathway alone have been studied in humans, this is the first assessment of a dual antagonist in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy subjects. The PK‐PD relationship was evaluated.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

ALPN‐101 demonstrated favorable safety and tolerability profiles and dose‐dependent PK and PD in healthy subjects. The dose‐PK‐PD analysis showed that the target saturation of ALPN‐101 can be well‐predicted based on PK data and the observed PD effects are consistent with the known biology of the CD28 and ICOS pathways.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results support further clinical development of ALPN‐101 and the PK‐PD relationship will guide dosing regimens in autoimmune and inflammatory diseases.