Targeting FLT3 with AGS62P1: A Potent Anti-Tumor ADC Unaffected by Kinase Activation Status

The article discusses FLT3, a receptor tyrosine kinase crucial for myeloid and lymphoid progenitor cells, and its involvement in acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL). FLT3 is frequently mutated in AML, with internal tandem duplications (ITD) and D835 point mutations leading to receptor activation. FLT3 small molecule inhibitors are effective against activated AML, but an antibody-drug conjugate (ADC) could provide a therapeutic option for all AML patients.

Researchers have developed AGS62P1, an innovative FLT3-specific ADC using p-acetyl phenylalanine (pAF) for site-specific conjugation. This ADC features a human gamma one antibody with pAF residues in the heavy chains, linked to a cytotoxic payload via an oxime bond. The resulting product has a uniform drug distribution and a strong binding affinity to FLT3, with potent in vitro cytotoxic activity against AML cell lines.

The anti-FLT3 ADC demonstrated high efficacy in AML tumor xenografts, significantly inhibiting tumor growth in both FLT3 ITD and non-ITD models. The study included further characterization of the antibody and ADC, such as ligand-receptor interactions, degradation, internalization, and apoptosis.

In conclusion, the site-specific ADC targeting FLT3 has shown potent anti-tumor activity in xenograft models, irrespective of FLT3 activation status. This new drug could offer a versatile approach to treating FLT3-expressing leukemia, independent of FLT3 genetic aberration. The study was presented at the 107th Annual Meeting of the American Association for Cancer Research, with the citation provided in the abstract.