SLV-404, an anti-RYK antibody-drug conjugate, is effective in Richter transformation patient-derived xenografts.

Richter transformation (RT), a highly aggressive lymphoma arising from a preexisting chronic lymphocytic leukemia, represents a major unmet clinical need. Recent data have shown that an antibody-drug conjugate (ADC) targeting the cell-surface pseudokinase ROR1 is effective in RT patients. In this work, we explored other members of the ROR1 family and focused on RYK as a novel therapeutic target. Transcriptomic analyses revealed that RYK is expressed across multiple lymphoma subtypes, including indolent and aggressive lymphomas, such as RT, while it is absent in peripheral blood mononuclear cells (PBMCs) from healthy donors. To increase the selectivity of the ADC for highly proliferating B-cell malignancies, as a payload we chose an inhibitor of topoisomerase I (TOP1), which is highly expressed in aggressive lymphomas while being undetectable in PBMCs from healthy donors. Based on these premises, we generated SLV-404, an ADC composed of a chimeric antibody directed against the extracellular domain of RYK, a cleavable linker, and the potent TOP1 inhibitor deruxtecan (DXd). In vitro studies in lymphoma cell lines and in cells obtained from RT patient-derived xenografts (RT-PDXs) consistently showed robust induction of apoptosis following SLV-404 treatment, while normal PBMCs were fully resistant. The antitumor activity of SLV-404 was then confirmed in vivo using subcutaneous and intravenous RT-PDX models. Treated animals survived significantly longer with markedly reduced tumor growth and tumor burden. Together, these findings identify RYK as a therapeutic target in aggressive RT and underline the potential of SLV-404 as an ADC-based strategy for the treatment of aggressive lymphomas.