Development of an anti-LAIR1 antibody-drug conjugate for acute myeloid leukemia therapy.

Acute myeloid leukemia (AML) is a severe blood cancer with an urgent need for novel therapies for refractory or relapsed patients. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), an immune suppressive receptor expressed on immune cells and AML blasts but minimally on hematopoietic stem cells (HSCs), represents a potential therapeutic target. But there has been limited research on therapies targeting LAIR1 for AML and no published reports on LAIR1 antibody-drug conjugate (ADC). We developed LA-057-MMAE, a first-in-class ADC, and evaluated its antitumor potential. LA-057-MMAE demonstrated strong binding to human LAIR1 with an affinity of 3.9 nM, efficient internalization of approximately 70 % within 4 h, and remarkable cytotoxicity against AML cells, with IC50 values of 0.22 nM for MV-4-11, 0.02 nM for U937, and 0.09 nM for HL-60 cells, respectively. In vivo, it achieved complete tumor regression in 100 % of MV-4-11 xenograft mice at 6 mg/kg, extending survival beyond 60 days. Our findings suggest that LA-057-MMAE, as a first-in-class treatment distinct from existing LAIR1 monoclonal therapies, could provide a groundbreaking therapeutic strategy for AML.