A First-in-Human (FIH) Phase 1 Study of the Anti-LILRB4 Antibody IO-202 in Relapsed/Refractory (R/R) Myelomonocytic and Monocytic Acute Myeloid Leukemia (AML) and R/R Chronic Myelomonocytic Leukemia (CMML)

Patients with myelomonocytic and monocytic AML are often resistant to current standards of care. LILRB4, an immunosuppressive myeloid checkpoint, is expressed in myelomonocytic and monocytic AML and CMML. Preclinical evaluation of a novel anti-LILRB4 IgG1 monoclonal antibody, IO-202, demonstrated 3 mechanisms of action: 1) activation of effector T-cells; 2) prevention of leukemic blast infiltration; and 3) killing of LILRB4-high blasts via ADCC and ADCP.

IO-202 exhibits high affinity binding to human LILRB4, blocking APOE binding and activation of LILRB4. Inhibiting this pathway activates T-cell cytotoxicity against leukemic cells, reversing T-cell suppression mediated by AML cells in vitro. In a syngeneic mouse AML model, IO-202 increases CD8+ T cells, resulting in tumor growth inhibition. In mouse xenograft models, IO-202 inhibits AML tumor growth, prolongs survival, and blocks tissue infiltration of leukemia cells. IO-202 depletes leukemic cells expressing high levels of LILRB4 in vitro through ADCC and ADCP. In cynomolgus monkeys IO-202 exhibited the expected PK profile. In a GLP 4-week repeated-dose IV toxicity study with a 10-week recovery period in cynomolgus monkeys, IO-202 was well-tolerated at all doses tested, up to 180 mg/kg/dose. IO-202-related microscopic findings were noted in the brain, spleen and lung; the microscopic finding of mild multifocal gliosis at ≥60 mg/kg/dose was considered adverse. At the end of the recovery period, all findings showed signs of complete or partial reversibility. TheNOAEL was 20 mg/kg, providing a sufficient safety margin for the clinical starting dose of 0.03 mg/kg. The nonclinical assessment provides a comprehensive understanding of IO-202 and is adequate to support its evaluation in the proposed Phase 1 study.

Study Design and Methods

Major inclusion criteria for the phase 1 study (NCT04372433) include: 1) Age > 18; 2) Relapsed AML with myelomonocytic or monoblastic/monocytic differentiation or CMML and has failed treatment with available active therapies; 3) adequate renal/hepatic function; and 4) ECOG 0-2.

Major exclusion criteria include: 1) HSCT within 60 days, on calcineurin inhibitors, or chronic GVHD; 2) chemotherapy, radiotherapy, or investigational agents within 7 days; 3) significant cardiac disease; 4) active infection; 5) uncontrolled CNS leukemia; and 6) hyperleukocytosis (> 25 x 10⁹/L, although hydroxyurea is permitted).

The primary objective is assessment of safety and tolerability at increasing doses of IO-202 to estimate the MTD or MAD, and select the RP2D. Secondary objectives include characterizing PK, immunogenicity, and preliminary anti-leukemia activity. Biomarker evaluation will include changes in blasts and immune cells, cytokine profiling, LILRB4 expression level and receptor occupancy, and MRD assessment.

Dose escalation will employ an accelerated titration scheme to minimize exposure to low-dose levels, with conversion to a 3+3 design with the occurrence of > Grade 2 AEs. The RP2D will be determined by the totality of data including the MAD or MTD, PK, PD, and AEs during a 28-day DLT evaluation period.

After RP2D determination, an expansion cohort will be enrolled to assess the preliminary efficacy of IO-202 in R/R myelomonocytic and monocytic AML. In addition to descriptive statistics for AEs, PK, PD, and response rates, a Bayesian estimation of DLTs will be performed to further assess safety. If there is a >80% probability of DLTs being > 20%, the study will be paused to further evaluate the safety findings.

A planned protocol amendment will evaluate combination therapies with IO-202, including IO-202 + azacitidine.