A First-In-Human Study Of Ky1044, A Fully Human Anti-Icos Igg1 Antibody As Monotherapy And In Combination With Atezolizumab In Patients With Selected Advanced Malignancies.

TPS2644 Background: The Inducible T-cell costimulator (ICOS/CD278) is related to the CD28 superfamily and is induced upon T cell activation. There is a hierarchical order of ICOS expression level, in which highly immunosuppressive TReg (CD4+Foxp3+) present in the tumor microenvironment (TME) are at the top level of expression and CD8 TEff cells are at the bottom level. In addition, ICOS expression on TRegs is higher in the TME than in the blood or spleen. Methods: KY1044, a fully human anti-ICOS IgG1 kappa monoclonal antibody, selectively binds to ICOS with high affinity (which is maintained at intratumoral acidic pH) and has a dual mechanism of action: it promotes the preferential depletion of intratumoral ICOSHigh TRegs resulting in an increase in the TEff:TReg ratio in the TME; and it stimulates ICOSLow TEff cells. Preclinical data demonstrate that KY1044 monotherapy or in combination with anti-PD-L1 is associated with immune cell activation and anti-tumor response. In order to validate the dual mechanism of action in vivo, studies in mice and cynomolgus monkeys were conducted. Firstly, KY1044 injected i.v. at doses up to 100 mg/kg weekly were well tolerated in non-human primates. In addition, pharmacodynamic studies in mice and cynomolgus monkey confirm preferential depletion of ICOSHigh cells. KY1044-CT01 is an open-labelled first in human Phase I/II study assessing the safety, tolerability, PK, PD and anti-tumor activity of KY1044 administered every 3 weeks (Q3W) as an i.v. single agent infusion and in combination with atezolizumab (1200 mg, Q3W IV) in adult patients with advanced/metastatic malignancies. The primary endpoint of the Phase I dose escalations, designed as sequential but overlapping arms of KY1044 monotherapy and combination with atezolizumab, is safety and tolerability. Secondary endpoints are the characterization of pharmacokinetic, pharmacodynamic and efficacy profiles in all patients. In the Phase II part, the primary endpoint is overall response rate (ORR), and the measure of clinical efficacy will be confirmed as per RECIST 1.1. and immune-related (ir)RECIST. An intensive biomarker plan is integral to the study design to underpin the phenotypic and molecular changes in both peripheral blood and tumor. Clinical trial information: NCT03829501.