GSPT1 degrader antibody conjugate, BLB-201, for the treatment of high-risk acute myeloid leukemia

Targeted degradation of GSPT1, a translation termination protein, is a novel approach for Acute Myeloid Leukemia (AML) treatment. We developed a degrader antibody conjugate (DAC) BLB-201 to (i) improve the systemic tolerability of GSPT1 degrader, and (ii) selectively kill AML blasts and leukemia stem cells expressing the tumor antigen, CD123/IL3RA. The BLB-201 DAC was optimized for activity, safety, physiochemical properties, and stability. BLB-201 rapidly degraded GSPT1 and caused cellular stress-driven apoptosis in AML cells, and showed high degree of homogeneity, solubility, and linker-payload stability in serum. A panel of CD123-positive cell lines and patient AML blast samples, with high-risk abnormalities, such as FLT3-ITD mutation, TP53 mutation and MLL1 gene re-arrangements, were evaluated for cell killing by BLB-201. BLB-201 was potent against CD123-positive AML cell lines but did not affect the viability of CD123-negative cells in the cell killing assays. BLB-201 had strong cytotoxic effects on patient AML blasts (n=17 samples) and leukemic stem cells ex vivo . In vivo , BLB-201 exhibited excellent synergy at low doses (0.1-0.3mg/kg) with clinical anti-AML agents (venetoclax, azacitidine and quizartinib) in systemic MV-4-11 and MOLM-13 models. In the systemic PDX models representing relapsed AML with high-risk mutations, BLB-201 monotherapy significantly suppressed circulating CD45+ AML cells, prolonged survival as well as produced complete response in combination with venetoclax and azacitidine regimen. As a single agent both in the in vitro and in CDX AML models, BLB-201 showed better efficacy compared to a CD33-targeted GSPT1 DAC benchmark. We did not observe any effects of BLB-201 on normal erythroid, megakaryocytic and myeloid cell differentiation from CD34+ hematopoietic stem cells in vitro , while the CD33-targeted antibody drug conjugate, gemtuzumab ozogamacin, was highly toxic in these assays. BLB-201 DAC allows selective targeting of CD123-positive AML blasts and leukemia stem cells, minimizing direct exposure of GSPT1 degrader to healthy tissues. This unique mechanism of action may improve response rates when combined with existing targeted therapies for AML patients with high-risk or relapsed/refractory disease.