ELA026: A Monoclonal Antibody for Rapid and Potent Myeloid and T Lymphocyte Depletion

ELA026, a fully human monoclonal IgG1 antibody, targets Signal Regulatory Proteins (SIRPs) on the surface of myeloid lineage cells and T cells. It was selected for its ability to bind SIRPs without hindering CD47 binding or SIRP signaling. The cynomolgus monkey has been identified as a relevant species for pharmacological studies due to its comparable cellular SIRP expression and similar response to ELA026 as humans, including potent antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP).

In vitro, ELA026 demonstrated a low effective concentration for inducing maximal ADCC and ADCP. In vivo studies in non-human primates (NHP) showed dose-dependent pharmacodynamic effects, including a rapid and significant reduction in circulating monocytes, granulocytes, and T cells. The duration of these effects was dose-dependent, with higher doses leading to longer-lasting cellular depletion. A minimum concentration of ~0.1 μg/mL was identified as necessary to maintain the pharmacodynamic effect, aligning with in vitro findings. All affected cell types were observed to recover to pre-dose levels within days post-treatment, indicating no impact on bone marrow hematopoiesis.

The study concluded that ELA026 binds to SIRP proteins on primary human monocytes and T cells, inducing potent ADCC and ADCP. In vivo administration in NHPs resulted in rapid depletion of SIRP-expressing cells, with a clear pharmacokinetic/pharmacodynamic relationship consistent with in vitro results. The pharmacodynamic effect was reversible upon treatment cessation, suggesting no long-term immunosuppression associated with ELA026 use. These findings support the clinical development of ELA026 for treating myeloid and T lymphocyte-driven disorders, such as secondary Hemophagocytic Lymphohistiocytosis (sHLH), for which there are currently no approved therapies. A Phase 1b trial to assess ELA026's efficacy in sHLH is ongoing.